Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Hueng-Chuen Fan
 + 4441 word(s) 4441 2021-12-20 04:20:04

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Fan, H. Telomeres and Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/20808 (accessed on 19 November 2024).
Fan H. Telomeres and Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/20808. Accessed November 19, 2024.
Fan, Hueng-Chuen. "Telomeres and Cancer" Encyclopedia, https://encyclopedia.pub/entry/20808 (accessed November 19, 2024).
Fan, H. (2022, March 21). Telomeres and Cancer. In Encyclopedia. https://encyclopedia.pub/entry/20808
Fan, Hueng-Chuen. "Telomeres and Cancer." Encyclopedia. Web. 21 March, 2022.
Telomeres and Cancer
Edit
This entry is adapted from the peer-reviewed paper 10.3390/life11121405

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation.

telomerase telomerase reverse transcriptase shelterin CST promoter mutations

1. Introduction

Cancer is notorious as it can attack any part of the body, rapidly grow beyond its usual boundaries, invade adjoining tissues, and spread to other organs, resulting in uncontrolled proliferation and eventually death. Nearly 10 million deaths were reported in 2020 from cancer, and the risk of getting cancer in a lifetime (before the age of 75 years) is 20% [1]. The most common newly-diagnosed cancers reported worldwide include breast (2.26 million), lung (2.21 million), and colorectal (1.98 million) cancers [1]. Approximately half of the newly diagnosed lung (57%) and pancreatic (52%) cancer cases in the United States are at an advanced or metastatic stage, and the majority of these patients with an early diagnosis of the disease eventually develop tumor progression [2]. The 5-year relative survival rates for advanced-stage cancers, such as lung, colorectal, liver, and pancreatic, remain low, ranging from 3% to 14% even after maximal surgical excision, radiation, chemotherapy, and hormone, immune, and targeted therapies [2]. Thus, none of the standard cancer treatments can completely cure patients at an advanced stage of the disease. Knowledge of the molecular mechanisms influencing tumor growth and invasiveness may lead to novel and effective therapies for the poor prognosis of late-stage cancers.
Cancer formation and progression is a genetic phenomenon with normal cells accruing genomic instability and thereby acquiring the ability to replicate indefinitely, which is the phenotype of immortality [3]. Telomerase, the immortality enzyme, is ubiquitous in all mammalian embryonic tissue and remains active in germs cells but is down-regulated in most somatic tissues [4]. As telomerase activity determines cellular proliferation, it must be tightly regulated to prevent the induction of carcinogenesis [5]. Telomerase reverse transcriptase (TERT), the catalytic subunit responsible for enzyme activity in telomerase, is the rate-limiting factor of human telomerase enzyme activity [5]. Two of the critical telomere-specific proteins involved in the regulation and maintenance of the telomere length are the shelterin and CST complexes [6].

2. Telomeres, a Genetic Time Bomb or a Biological Clock

Human telomeres comprise a hexameric nucleotide repeat sequence (TTAGGG) that is initially double-stranded DNA (dsDNA) but ends with a single-stranded DNA (ssDNA) overhang (G’-overhang). The extended 5′ to 3′ strand contains the G-rich telomeric repeats and is referred to as the G-strand, while the 3′ to 5′ strand is defined as the C-strand [7][8]. During the cell division cycle, the eukaryotic DNA polymerase is unable to completely replicate the sequences at the chromosomal ends. This is because RNA primers attach at the lagging strand during the synthesis of Okazaki fragments, and the resulting shedding RNA leads to telomere shortening [9]. The so-called “end replication problem” results in eventual apoptosis, cellular senescence, and cell cycle arrest [10][11]. Additionally, chromosomes lacking the “capping structure” tend to get truncated and fused with other chromosomes [12]. As such, telomeres are also considered a genetic time bomb or a biological clock for cellular aging [13].
As approximately 50–200 bases are lost from the terminal sequence of chromosomes each time a cell divides [14], and more than a couple of trillion telomere sequences are in the human genome, the spatiotemporal expression of telomerase must be tightly regulated in humans. Apart from the shedding RNA and the generation of the 3′ overhang by the sequence-specific exonuclease activity to resect back the 5′end of telomeres [15], telomere shortenings can occur, irrespective of cell replication, due to accumulative oxidative stress [16], host age [17], gender [18], sex hormones [19], and lifestyle factors, such as the lack or presence of exercise [20], obesity and weight loss [21], smoking [22], and unhealthy diets [23]. However, short telomeres not only result in genomic loss [24][25], shorter lifespan [26][27] and contribute to diseases such as coronary heart disease [28], heart failure [29], osteoporosis [30], diabetes [31], but can also result in genomic instability and elevated telomerase activity, leading to a potential cancer predisposition factor [32]. Hence, proper telomere maintenance is critical for human life.

3. The Shelterin Complex

Telomeres are protected by a highly conserved mammalian nucleoprotein complex called shelterin (telosome). This nucleoprotein complex can minimize telomere fragility by enabling DNA replication at the telomeric repeats [33][34]. The shelterin complex can allow DNA to form a lasso-like structure with a telomeric loop (T-loop) and a displacement loop (D-loop) that then shields the 3′-end from DNA damage and blocks the activation of the DNA repair mechanisms, such as ataxia-telangiectasia Rad3-related (ATR)-mediated DNA damage kinase signaling and ataxia-telangiectasia mutation (ATM) kinase cascades, as well as unwanted repair reactions [35]. The shelterin complex anchors to both ssDNA and dsDNA [33][36][37][38]. The shelterin complex and other protein complexes specific to the telomere can detect and react to changes in telomere length in order to maintain the proper length of telomeres [39][40] (Figure 1). However, in cancers, mutations in the shelterin complex that cause telomere dysfunction and dysregulation are very common [41].
Figure 1. A graphic presentation of telomeric DNA and the proteins that form the shelterin complex. Telomeres are capping structures and are situated at the ends of linear chromosomes. Telomeric DNA, TTAGGG at the chromosome ends, and the complementary DNA strand sequence AATCCC form an extended region of dsDNA ending with a ssDNA G-rich overhang. The 3′ G-rich overhang enables telomeric DNA to form a secondary structure in which the 3′ single-stranded overhang folds back and displaces a strand in the homologous dsDNA TTAGGG region, to create a D-loop that protects the 3′-end from being identified as damaged DNA, thereby preventing the activation of the ataxia-telangiectasia mutation and Rad3-related (ATM/ATR) damage response pathways. The shelterin complex comprises six telomeric proteins: TRF1, TRF2, RAP1, TIN2, POT1, and TPP1. The complex enables the telomeric 3′-overhang/G-tail to fold into a lasso-like structure with a telomeric loop (T-loop) that protects the 3′-end from being recognized for DNA damage and blocks the DNA damage response.
The shelterin complex is composed of six subunits, namely the telomere repeat-binding factor 1(TRF1), telomere repeat-binding factor 2 (TRF2), repressor activator protein 1(RAP1), TRF1-interacting nuclear factor 2(TIN2), TINT1/PTOP/PIP1(TPP1), and the protection of telomeres-1(POT1) [42][43].

4. The CST Complex

The CST complex comprises telomere-specific proteins that regulate telomere length replication and maintenance. The CST complex was initially identified in Saccharomyces cerevisiae and later in vertebrates [44][45][46].

4.1. Yeast CST Complex

Saccharomyces CST complexisa trimeric nucleoprotein complex composed of cell division control protein 13(CDC13), suppressor of CDC thirteen 1 (STN1), and telomeric pathway with STN1 (TEN1) [47]. During cell budding, the CST complex is known as the CDC13-STN1-TEN1 complex; however, fission yeast only contains STN1 and TEN1 [48]. Deletions affecting CDC13, STN1,or TEN1 make budding yeast cells unviable [47]. Therefore, the yeast CST complex is crucially important and may possess evolutionarily conserved functions in DNA replication [49]. Yeast CST complex is structurally related to the heterotrimeric replication protein A (RPA)-complex [45], which is a heterotrimeric ssDNA-binding protein complex composed of replication factor A1 (Rfa1), Rfa2, and Rfa3 (Figure 2A) [50].

4.2. Human CST Complex

As with yeast, the human CST complex comprises the conserved telomere maintenance component 1 (CTC1), STN1, and TEN1 (Figure 2B), and each subunit is present in the stoichiometric ratio of 1:1:1 [51][52][53]. It localizes at the chromosomal ends, preferentially to G-rich and repetitive elements [54], and can maintain telomere length [46][55]. Human CST is an RPA-like ssDNA-binding protein that has primarily been characterized as a telomere replication factor [56]. RPA is crucial for replication, repair, and recombination and is involved in multiple protein–protein interactions [57], telomere metabolism [45], and chromosome maintenance [58]. The human RPA complex comprises RPA70, RPA32, and RPA14 [50][59]. (Table 1).
Figure 2. Comparison of (A) S. cerevisiae Rfa and CST with (B) human RPA and CST. Domain structures of Rfa and CST. DBD: DNA-binding domain;OB: OB-fold domain; RD: recruitment domain; TR2: the single RAD51-binding domain; WH: winged helix domain; wHTH: winged helix-turn-helix domain.
Table 1. Comparison of CST and RPA.

CST.

Component

aa

OB

wH

wHTH1

Functions

References
           

1. Binding to ssDNA.

[52][60][61][62][63][64]
 

CTC1

1217

7

0

0

2. Binding to ssDNA-dsDNA junctions.

[65]

STN1

368

1

0

2

3. Recognize different specialized DNA structures at DNA replication and breakage sites.

[66]

TEN1

123

1

0

0

4. Acting synergistically with ATR to maintain telomere length and genome stability.

[67]

5. Stimulating Polα.

[68][69][70]

6. Helping in C-strand fill-in.

[63][71]

7. Preventing the accumulation of G4.

[66]

8. Preventing telomeric DNA damage.

[58][61]

9. Interacting with the MCM and disrupting binding of CDT1 to MCM, leading to decreased origin licensing.

[72]

10. Interacting with AND-1.

[73]

11. Inhibiting telomerase.

[65][70][71][74][75]

RPA

          

1. Binding ssDNA.

[76]
 

RPA70

616

4

0

0

2. Activating the ATR signaling.

[77]

RPA32

270

1

1

0

3. Activating the helicase.

[78]

RPA14

121

1

0

0

4. Unwinding G4.

[79]

5. Involved in DNA replication, recombination, and repair.

[80]

6. Activating BLM’s bidirectional DNA unwinding.

[81]

7. Modulating the fork remodeling enzyme activity.

[82]

8. Enhancing primase.

[83]
Similar to CST, RPA has several functional features:1. Binding ssDNA: RPA binds and protects ssDNA from cleavage by nucleases and recruits repair proteins to initiate DNA damage responses [76]. 2. Activating the ATR signaling: Replication stress (RS) is a condition when the replication fork progression and/or DNA synthesis is stalled or slowed [77]. The RPA-coated ssDNA serves as a main activation platform for recruiting ATR-ATR-interacting protein (ATRIP) to the stalled forkin RS [78]. Activated ATR-ATRIP phosphorylates and activates Checkpoint kinase 1(CHK1), which induces cell cycle arrest to allow DNA repair, fork stabilization, or replication start [84]. 3: Activating the helicase: RPA binding stimulates the accumulation of the human DNA helicase B on chromatin in replication stress [85].4. Unwinding G4: RPA binding promotes WRN activity and multiple RPA binding makes WRN a super-helicase on G4 unwinding [79]. 5. Involvement in DNA replication, recombination, and repair: BLM forms a complex with topoisomerase IIIα, RPA, and several factors involved in functions related to DNA replication, recombination, and repair [80]. 6. Activating BLM’s bidirectional DNA unwinding [81]. 7. Modulating the fork remodeling enzyme activity: SMARCAL-1(SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is a fork-remodeling enzyme. RPA binds to ssDNA at the fork junction, creating an optimal DNA-protein substrate for SMARCAL-1. However, when the RPA binding to the ssDNA formed at the leading strand stimulates the SMARCAL1-mediated fork remodeling activity, the RPA binding at the lagging strand inhibits the SMARCAL1 activity [82]. 8. Enhancing primase: RPA enhances primase activity at forks [83] (Table 1).

4.3. CTC1

CTC1 and CDC13 are the largest subunits of the human and budding yeast CST complexes, respectively. As the CDC13 null strain cannot be generated in yeast cells [86], it is believed that CDC13 is essential for cell viability. Although STN1 and TEN1 are highly conserved [87], the genomic sequences and functions of CDC13 in yeast and that of CTC1 in humans are different [53]. Structurally, CDC13 consists of OB1, OB2, OB3, and OB4 (Figure 2A). The roles of these OBs include ssDNA binding, protein–protein interactions, DNA polymerase α-primase binding, and CDC13 homo-dimerization [88][89][90]. However, a recent study analyzing the crystal structures of the CST complex of Kluyveromyces lactis suggests that OB2 and OB4 are required for the CDC13–STN1 interaction that assembles CST in a 2:2:2, instead of1:1:1, stoichiometry [91].
Human CTC1 has OB-A, OB-B, OB-C, OB-D, OB-E, OB-F, and OB-G (Figure 2B). The C terminus of CTC1 (OB-D through OB-G) acts as a platform to assemble STN1 and TEN1 [51]. STN1 (STN1 OB and the first winged helix-turn-helix [wHTH1] domain of STN1) interacts with CTC1 at two interaction sites, CTC1 OB-G and CTC1 OB-E, respectively (Figure 2B) [51]. Structural analyses have shown that CTC1 OB-G is similar to the OB-C of RPA70 and not CDC13 [92]. The CDC13 recruitment domain (RD) contains numerous phosphorylation sites [93][94][95][96][97]. Phosphorylated CDC13 RD enhances the ever shorter telomere 1 (Est1), a component of the yeast telomerase holoenzyme binding and telomerase recruitment to telomeres [93][94]. Est1 is present in humans and a report shows that the expression of Est1 is significantly reduced in B-chronic lymphocytic leukemia [98]. Dephosphorylated CDC13 RD promotes CST complex assembly to bind and cap the ends of chromosomes [94][95][96][99]. Human CTC1 represses the elongation of telomerase by binding to telomerase-extended telomeres thus preventing telomerase activity [71]. CDC13–Est1 and POT–TPP1 are essential in directing telomerase to the chromosomal ends [100][101]. CTC1 interacts with TPP1 to compete with TPP1–POT1 for binding at the telomeric 3′ tail and sequestrate the single-stranded telomeric overhang to inhibit the telomerase extension reaction [53][71]. In humans and yeast, the CST complex prevents 3′ overhangs via boosting the fill-in synthesis [75][102]. Yeast CDC13 deficiency causes genome stability and unstable chromosomes [103]. Dyskeratosis congenita (DC) and Coats plus syndrome (CPS) are two uncommon diseases associated with mutations that affect the CST complex. CPS is an autosomal recessive, systemic disorder characterized by intrauterine growth retardation, bilateral exudative retinal telangiectasias, intracranial calcifications, intracerebral cysts, extra-neurological features, including osteopenia with a tendency of fractures and gastrointestinal bleeding, and portal hypertension [104]. Symptoms of DC include increased cancer incidence, bone marrow failure, lacy reticular pigmentation of the upper chest and/or neck and oral leukoplakia [105]. Changes that occur as a result of CTC1 and STN1 mutations include telomere DNA replication defects, genome instability, defects in interactions with Polα, chromosome breakage, and an accumulation of the ssDNA gaps of telomeric DNA [47][106][107].

4.4. STN1

Human STN1 was initially named as Polα accessory factor44 as STN1 has been shown to enhance primase and up-regulate the recruitment of Polα for lagging strand DNA replication [68][108]. Structurally, the yeast STN1 consists of an OB-5 domain and two wHTH motifs, wHTH1 and wHTH2, which may involve Polα and CDC13 binding [51]. The N-terminus of STN1 binds to TEN1, while the C-terminus associates with both CDC13 and Pol12 (the B subunit of Polα) [109][110].The STN1 and TEN1 are enlisted to telomere ends via direct association with CDC13. Both STN1 and TEN1 display relatively poor telomeric DNA-binding affinities [111]. In humans, STN1 functions as an adapter between TEN1 and CTC1 [55], and the STN1 N-terminal interacts with CTC1 OB-G and the C-terminal with CTC1 OB-E [51]. Fluorescence investigation has demonstrated that the STN1-binding sites are prone to DNA breakage in STN1 deficient cells under replication stress, leading to chromosome fragmentation [54].

4.5. TEN1

Of the CST components, TEN1is the smallest with a single OB fold [51]. Yeast TEN1 may promote the activity of CDC13 and bind to telomeric ssDNA to enhance the DNA-binding activity of CDC13 [112]. TEN1 in humans is to stabilize the binding of CTC1-STN1to ssDNA and to support C-strand fill-in after G-strand extension by telomerase [65]. Human TEN1 attachment to CTC1 OB-G is facilitated by the OB of STN1 [51]. Human TEN1mutant strain proteins are unable promote the binding of CDC13 to telomeres in vitro, indicating that TEN1 improves the telomeric DNA-binding activity of CDC13 that then negatively affects the telomere length [65]. Knockout TEN1 cells show gradual telomere shortening comparable to that resulting from telomerase deficiency [65], indicating that TEN1 is crucial for the maintenance of telomere length. In addition to ensuring telomere stability [52], TEN1 and STN1 can rescue replication fork stalling during replication stress [55][58][113].
CDC13, STN1, and TEN1 are essential for cell viability and regulating telomere length. Subunit mutations resulting in loss-of-function can cause an accumulation of telomeric ssDNA and result in abnormal elongation of the telomeres, indicating that these three subunits are critical to the health of organisms with the CST complex [6][51][60][74]. The interactions between POT1-TPP1 and CST can significantly affect the telomere length and may result in telomere length dysregulation and cancer development, such as familial glioma [114], melanoma [115], chronic lymphocytic leukemia [116] and breast cancers [117][118], stomach cancers [117], and parathyroid cancers [119].

5. Telomerase: Breaking through the Limitation of Replication

Telomerase, the enzyme responsible for lengthening the telomeres, can extend the cellular lifespan or induce immortalization [1]. Typically, in healthy adult somatic cells, telomerase is inactive to avoid uncontrolled cellular proliferation [2], whereas in approximately 90% of human tumors, telomerase is up-regulated or reactivated to help tumor cells survive and multiply [120]. However, developing embryos, reproductive cells, activated immune cells, bone marrow, and adult stem cells show high telomerase activity [18].

6. Telomerase-Based Anti-Cancer Strategy

The fundamental concept of cancer immunotherapy is based on manipulating the host immune system to attack the cancer cells. Although there are several novel cancer immunotherapy strategies, vaccine-based strategies are the most attractive and promising ones. However, it is very difficult to target tumor-associated antigens on the surface of tumor cells but not on that of the normal cells because of the heterogeneity and overlapping expression of these antigens in both cancers and healthy tissues [121]. As cancer cells lacking telomerase can undergo spontaneous remission, telomerase inhibition in most cancers may shed light on a potentially successful therapeutic strategy [122]. As telomerase is an HLA class-I antigen and can stimulate a cell-mediated immune response by inducing cytotoxic T-cells, numerous novel approaches have recently been developed to attenuate/inhibit the functions of the telomerase that impact cancer. Vaccination against telomerase is tolerable and safe and has been shown to induce excellent immunological responses associated with increased survival in several cancer types.

6.1. GV1001

The GV1001, an HLA class II-restricted peptide vaccine, is composed of 16 amino acids (TERT611–626:EARPALLTSRLRFIPK) derived from the hTERT active site [32][123]. GV1001 was the first TERT peptide vaccine to be evaluated for treating advanced pancreatic cancer, lung carcinoma, melanoma, and liver carcinoma in clinical trials [123][124][125][126][127][128][129][130]. GM-CSF can enhance immunological response through the recruitment and maturation of dendritic cells and the activation of macrophages, neutrophils, and NK cells [131]; therefore, GV1001in combination with GM-CSF can result in a high frequency of immune responder s [32][124]. GV1001 can induce an efficient hTERT-specific T-cell activation and penetrate within tumor cells through the cell membrane [132]. Therefore, it can recognize the antigen-presenting cells that are internalized in the tumor and lymph nodes [124]. GV1001 can induce cancer cell apoptosis [133][134][135] and down-regulate heat shock proteins, hypoxia-inducible factor-1, and vascular endothelial growth factor to enhance its anti-tumor effect [132][134][136]. Although GV1001 is theoretically suitable for most cancers, a report suggests that the GV1001 vaccination is not effective in cutaneous T-cell lymphoma [137], and another report indicates that GV1001 cannot induce any specific immune responses in patients with advanced HCC [125], and the addition of GV1001 to chemotherapy (gemcitabine and capecitabine) did not show any significant clinical benefits [128]. Patients with tuberculosis or receiving tuberculin may not be suitable for GV1001 vaccination because the evoked immune response against mycobacterial peptides may be so dominant as to suppress the immune response against the hTERT peptide [126].

6.2. GX301

The GX301 vaccine contains four immunogenic peptides (hTERT540–548: ILAKFLHWL; hTERT611–626: EARPALLTSRLRFIPK; hTERT672–686: RPGLLGASVLGLDDI, and hTERT766–780: LTDLQPYMRQFVAHL) that can bind both HLA class I and II; GX301 also contains two complementary adjuvants, Montanide ISA-51 and Imiquimod. Each GX301 administration consists of four intradermal injections (a fixed hTERT peptide dose, 500 µg)—one injection for each hTERT peptide—given at the same time and followed by topical application of imiquimod [138]. Montanide can protect the degradation of the peptides by tissue proteases, enhance peptide uptake by intradermal dendritic cells, induce interferon- γ release by innate immunity cells, and increase the expression of major histocompatibility complex (MHC) by tumor cells [139]. Imiquimod can activate the Toll-like receptor-7 and receptor-8 and induce the activation and maturation of dendritic cells [140]. The immunogenicity of GX301 was demonstrated in an ex vivo study in which circulating T-cell responses to its hTERT peptides were detected in all subjects [138]. A phase I trial of GX301 has provided evidence of vaccine-specific immune response in patients with stage IV prostate and kidney cancer, and prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunologic responses [138]. A phase II, randomized, parallel-group, open-label, multicenter trial (EudraCT: 2014-000095-26 and ClinicalTrials.gov Identifier: NCT02293707) has demonstrated that all the patients showed good immune responses to at least one of the peptides. The overall response was more for the multi-peptide vaccines than the single-peptide vaccines [141], suggesting that the four GX301 peptides endow a cumulative epitope pattern wide enough for inducing telomerase-specific peripheral T-cell reactivity in most individuals. A phase II, multicenter, randomized, parallel-group, open-label trial (EudraCT:2014-000095-26 and ClinicalTrials.gov Identifier:NCT02293707) was designed to comparatively analyze the safety and immunological response to GX301 regimens in castration-resistant prostate cancer patients with response/disease stability after docetaxel chemotherapy. Although the results indicate that the GX301 cancer vaccine is safe and 95% of the patients showed at least one vaccine-specific immune response, the overall survival did not differ between immunological responders and non-responders [142].

6.3. UV1

UV1 is a second-generation, multi-peptide vaccine constituted by three hTERT-derived peptides (hTERT652–665: AERLTSRVKALFSVL; hTERT660–689: ALFSVLNYERARRPGLLGASVLGLDDIHRA and hTERT691–705: RTFVLRVRAQDPPPE) [124]. In phase I and IIa trials, UV1 was administered along with GM-CSF for six months in patients with metastatic prostate cancer in combination with radiotherapy and androgen deprivation treatment (ADT). A total of 85.7% of patients showed an immune activation and 64% showed reduced levels of the prostate-specific antigen (PSA). In addition, 45% of the patients showed no evidence of the disease at the end of the trial [143]. Several checkpoint inhibitors, including Ipilimumab (anti-CTLA-4) or pembrolizumab (anti-PD-1) in melanoma patients (NCT02275416 and NCT03538314, respectively) and ipilimumab in association with nivolumab (anti-PD-L1) in patients affected by mesothelioma (NIPU trial, NCT04300244) have been singly or multiply used in combination with UV1 in clinical trials. The results showed that the treatment of UV1 together with these checkpoint inhibitors were safe and well-tolerated, and no severe allergic reactions were observed [144][145][146]. The NIPU trial is still ongoing and the primary end-point is expected to be analyzed in 2022.

6.4. Vx-001

Vx-001 is a peptide-based cancer vaccine consisting of two peptides: hTERT-derived low-affinity cryptic hTERT peptide: TERT 572 (RLFFYRKSV; ARG-Vx001) and its optimized mutant hTERT peptide: TERT 572Y (YLFFYRKSV; TYR-Vx001), which has an enhanced affinity to MHC class I molecules as the first amino acid was replaced with a tyrosine residue [147]. The antitumor efficacy and safety of Vx-001 has also been investigated in phase I/II clinical trials for different cancers, such as melanoma, bile duct cancer, breast cancer, and lung cancer. Results of these trials show that Vx-001may elicit a specific and possibly optimal cytotoxic T cell response against hTERT-expressing tumor cells and has improved clinical outcomes in clinical trials without any relevant toxicity [148][149][150][151].
Collectively, the hTERT-vaccine clinical trials indicate that these immunotherapies may represent a promising approach in cancer treatment. Apart from the TERT peptide vaccines, several novel immunotherapies, including the dendritic cell-based tumor vaccine, such as GRNVAC1 [151] and GRNVAC2 [152][153]; Tumor Antigen Presenting Cells (TAPCells) vaccines [154]; DNA vaccines such as phTERT [155], INVAC-1 [156]; adenovirus type 6 of an anticancer vaccine expressing hTERT, such astheV934/V935 vaccine [157]; gene-modified T-cell therapy, such as the use of tumor antigen-specific T-cell receptors originating from tumor-specific T cells or their clones [158][159]; the use of a chimeric antigen receptor (CAR) [160][161]; the molecules inhibiting Ras farnesylation [162], and hTERT-expressing human umbilical endothelial cells (HUVEC-TERTs) [163], may be effective without prominent toxicity.

7. Alternative Lengthening of Telomere (ALT)

7.1. ATRX and DAXX

Even with these new therapies, there have been certain cancers that can evade treatment by using an alternative lengthening of the telomere (ALT) mechanism. ALT is a telomerase-independent mechanism that uses recombination-dependent pathways to increase telomere length [164]. ALT is present in non-neoplastic tissues and in stromal, endothelial, and epithelial cells [165] and in approximately 10-15% of cancers [166], and it is common in sarcoma and glioma [167][168]. In the absence of telomerase, the ALT pathway uses a homologous recombination-based DNA replication mechanism to gain immortality. ALT activation required two chromatin-remodeling factors: the α-thalassemia X-linked intellectual disability (ATRX) and the death domain-associated protein (DAXX) [167][169]. DAXX was initially describe as a Fas death receptor binding protein [170]. ATRX is widely expressed and is a multi-functional factor involved in chromatin organization, DNA methylation, and transcriptional regulation [171]. Mutations in ATRX result in α-thalassemia ATRX syndrome, which is characterized by severe developmental delays, peculiar facial hypotonia and a characteristic mouth, intellectual impairment, genital anomalies ranging from undescended testes to ambiguous genitalia, and anemia secondary to α-thalassemia [172]. Patients with this syndrome may present long telomeres, which may be due to either improper maintenance of telomeric heterochromatin, improper resolution of replication stress at telomeres, or both by the mutation of ATRX [173].

7.2. Correlation between the Loss-of-Function of ATRX/DAXX and ALT in Cancer

The mutated ATRX gene is frequently detected in several tumors, including adrenocortical carcinoma, gliomas, GBM, neuroblastoma, and osteosarcoma [169], and pancreatic neuroendocrine tumors(panNETs), which are a group of endocrine tumors arising in the pancreas. PanNETs are among the most common neuroendocrine tumors. Functioning panNETs include insulinoma, gastrinoma, vasoactive intestinal peptide tumors (VIPoma), glucagonoma, and others that produce specific hormonal hypersecretion syndromes. Endocrine testing, imaging, and histological evidence is necessary to accurately diagnose panNETs. PanNETs may or may not cause signs or symptoms; however, as most panNETs may have malignant potential, an aggressive therapeutic approach for panNETs, including surgery, locoregional therapy, systemic therapy, and complication control, is required [174]. A report showed that 43% of panNETs contained the mutated ATRX or DAXX [175]. A correlation between the loss-of-function of ATRX/DAXX and the ALT phenotype in panNETs was found [176] and ATRX was proposed to serve as the primary suppressor of ALT [177]. Furthermore, when ATRX was reintroduced into ALT-positive ATRX-negative cell lines it was found to eliminate ALT-associated phenotypes [178][179]. Gliomas with wild-typeTERT promoters often present ATRX mutations to activate ALT [180]. A fibrosarcoma cell line (HTC75), which is telomerase-positive, can be converted to an ALT-mediated telomere elongation mechanism through TERT knockout, and the subsequent changes result in telomeric DNA damage and disruption of the ATRX/DAXX complex, indicating a negative correlation between mutations affecting TERT and ATRX/DAXX [167]. Consequently, telomeric DNA damage can reduce the compaction of telomeric chromatin, resulting in the production of altered telomeric DNA sequences. This in turn activates a telomere-specific DDR pathway [12][179], which can stimulate the homology-directed synthesis of telomeric DNA. However, cancer cells can circumvent cell death caused by an absence of telomerase or dysfunction by switching from telomerase-dependent to ALT-mediated telomere lengthening [181][182].

7.3. Targeting Telomerase Activity and the ATRX/DAXX Complex

Direct and indirect approaches to targeting telomerase activity and the ATRX/DAXX complex could prove effective. Direct approaches include immunotherapy specifically targeting TERT tumor-associated antigens, such as anti-sense oligonucleotides (e.g., Imetelstat/GRN163L) and small-molecule inhibitors (e.g., BIBR1532) and small molecule inhibitors could be used to bind telomerase and inhibit telomere elongation. Indirect techniques, such as G-quadruplex stabilizers (e.g., RHPS4, Telomestatin, TMPyP4, CX-3543/quarfloxacin), which are designed to block telomerase activity, are promising [183]. The G-rich oligos, which homolog to the telomeric overhang that forms the G4 structures, cause telomere dysregulation and a decreased proliferation rate, enhance apoptosis, and reduce expression of the TERT within melanoma cells [184].An alternative approach is based on telomere uncapping, using nucleoside analogs(e.g., 6-thio-dG) that rapidly affect telomere dysfunction, quickly triggering cancer cell death [185]. In addition, other factors, such as transcriptional, posttranscriptional, and epigenetic modifications can affect the activation or silencing of TERT; however, the effects are poorly understood in somatic, cancer, and stem cells. Epigenetic regulators, such as non-coding RNAs, histone modification, and DNA methylation, are now seen as crucial components for the regulation of telomeres and telomerase activity [186] and unlocking the epigenetic mechanisms associated with telomerase regulation could see advances in cancer diagnosis, treatment, and prognosis [187]. Convergently, a multipronged treatment strategy can maximize anti-tumor effects.

References

  1. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer statistics for the year 2020: An overview. Int. J. Cancer 2021, 149, 778–789.
  2. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin. 2021, 71, 7–33.
  3. Vogelstein, B.; Kinzler, K.W. The Path to Cancer—Three Strikes and You’re out. N. Engl. J. Med. 2015, 373, 1895–1898.
  4. Krupp, G.; Bonatz, G.; Parwaresch, R. Telomerase, immortality and cancer. Biotechnol. Annu. Rev. 2000, 6, 103–140.
  5. Cong, Y.-S.; Wright, W.E.; Shay, J.W. Human Telomerase and Its Regulation. Microbiol. Mol. Biol. Rev. 2002, 66, 407–425.
  6. Lim, C.J.; Cech, T.R. Shaping human telomeres: From shelterin and CST complexes to telomeric chromatin organization. Nat. Rev. Mol. Cell Biol. 2021, 22, 283–298.
  7. De Lange, T. How telomeres solve the end-protection problem. Science 2009, 326, 948–952.
  8. Meyne, J.; Ratliff, R.L.; Moyzis, R.K. Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proc. Natl. Acad. Sci. USA 1989, 86, 7049–7053.
  9. Lundblad, V. Telomere end processing: Unexpected complexity at the end game: Figure 1. Genes Dev. 2012, 26, 1123–1127.
  10. Gong, J.; Costanzo, A.; Yang, H.-Q.; Melino, G.; Kaelin, W.G., Jr.; Levrero, M.; Wang, J.Y.J. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 1999, 399, 806–809.
  11. Stiewe, T.; Putzer, B.M. P73 in apoptosis. Apoptosis 2001, 6, 447–452.
  12. O’Sullivan, R.J.; Karlseder, J. Telomeres: Protecting chromosomes against genome instability. Nat. Rev. Mol. Cell Biol. 2010, 11, 171–181.
  13. Lopez-Otin, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell 2013, 153, 1194–1217.
  14. Zhao, Y.; Abreu, E.; Kim, J.; Stadler, G.; Eskiocak, U.; Terns, M.P.; Terns, R.M.; Shay, J.W.; Wright, W.E. Processive and Distributive Extension of Human Telomeres by Telomerase under Homeostatic and Nonequilibrium Conditions. Mol. Cell 2011, 42, 297–307.
  15. Li, B.; Reddy, S.; Comai, L. Sequence-specific processing of telomeric 3′ overhangs by the Werner syndrome protein exonuclease activity. Aging 2009, 1, 289–302.
  16. Muraki, K.; Nyhan, K.; Han, L.; Murnane, J.P. Mechanisms of telomere loss and their consequences for chromosome instability. Front. Oncol. 2012, 2, 135.
  17. Frenck, R.W., Jr.; Blackburn, E.H.; Shannon, K.M. The rate of telomere sequence loss in human leukocytes varies with age. Proc. Natl. Acad. Sci. USA 1998, 95, 5607–5610.
  18. Dalgård, C.; Benetos, A.; Verhulst, S.; Labat, C.; Kark, J.D.; Christensen, K.; Kimura, M.; Kyvik, K.O.; Aviv, A. Leukocyte telomere length dynamics in women and men: Menopause vs age effects. Int. J. Epidemiol. 2015, 44, 1688–1695.
  19. Coburn, S.B.; Graubard, B.I.; Trabert, B.; McGlynn, K.A.; Cook, M.B. Associations between circulating sex steroid hormones and leukocyte telomere length in men in the National Health and Nutrition Examination Survey. Andrology 2018, 6, 542–546.
  20. Arsenis, N.C.; You, T.; Ogawa, E.F.; Tinsley, G.M.; Zuo, L. Physical activity and telomere length: Impact of aging and potential mechanisms of action. Oncotarget 2017, 8, 45008–45019.
  21. Welendorf, C.; Nicoletti, C.F.; Pinhel, M.A.D.S.; Noronha, N.; de Paula, B.M.F.; Nonino, C.B. Obesity, weight loss, and influence on telomere length: New insights for personalized nutrition. Nutrition 2019, 66, 115–121.
  22. Salihu, H.M.; Pradhan, A.; King, L.; Paothong, A.; Nwoga, C.; Marty, P.J.; Whiteman, V. Impact of intrauterine tobacco exposure on fetal telomere length. Am. J. Obstet. Gynecol. 2015, 212, 205.e1–205.e8.
  23. Leung, C.W.; Fung, T.T.; McEvoy, C.T.; Lin, J.; Epel, E.S. Diet Quality Indices and Leukocyte Telomere Length Among Healthy US Adults: Data from the National Health and Nutrition Examination Survey, 1999–2002. Am. J. Epidemiol. 2018, 187, 2192–2201.
  24. Calado, R.T.; Young, N.S. Telomere diseases. N. Engl. J. Med. 2009, 361, 2353–2365.
  25. Jacobs, J.J.L. Loss of Telomere Protection: Consequences and Opportunities. Front. Oncol. 2013, 3, 88.
  26. Farzaneh-Far, R.; Cawthon, R.M.; Na, B.; Browner, W.S.; Schiller, N.B.; Whooley, M.A. Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: Data from the heart and soul study. Arterioscler. Thromb. Vasc. Biol. 2008, 28, 1379–1384.
  27. Yang, Z.; Huang, X.; Jiang, H.; Zhang, Y.; Liu, H.; Qin, C.; Eisner, G.M.; Jose, P.; Rudolph, L.; Ju, Z. Short Telomeres and Prognosis of Hypertension in a Chinese Population. Hypertension 2009, 53, 639–645.
  28. Yeh, J.-K.; Lin, M.-H.; Wang, C.-Y. Telomeres as Therapeutic Targets in Heart Disease. JACC Basic Transl. Sci. 2019, 4, 855–865.
  29. Sharifi-Sanjani, M.; Oyster, N.M.; Tichy, E.D.; Bedi, K.C., Jr.; Harel, O.; Margulies, K.B.; Mourkioti, F. Cardiomyocyte-Specific Telomere Shortening is a Distinct Signature of Heart Failure in Humans. J. Am. Heart Assoc. 2017, 6, e005086.
  30. Valdes, A.M.; Richards, J.B.; Gardner, J.P.; Swaminathan, R.; Kimura, M.; Xiaobin, L.; Aviv, A.; Spector, T.D. Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos. Int. 2007, 18, 1203–1210.
  31. Grunnet, L.G.; Pilgaard, K.A.; Alibegovic, A.; Jensen, C.B.; Hjort, L.; Ozanne, S.; Bennett, M.; Vaag, A.A.; Brøns, C. Leukocyte telomere length is associated with elevated plasma glucose and HbA1c in young healthy men independent of birth weight. Sci. Rep. 2019, 9, 7639.
  32. Jafri, M.A.; Ansari, S.A.; Alqahtani, M.H.; Shay, J.W. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med. 2016, 8, 69.
  33. De Lange, T. Shelterin: The protein complex that shapes and safeguards human telomeres. Genes Dev. 2005, 19, 2100–2110.
  34. Diotti, R.; Loayza, D. Shelterin complex and associated factors at human telomeres. Nucleus 2011, 2, 119–135.
  35. Chen, L.-Y.; Liu, D.; Songyang, Z. Telomere Maintenance through Spatial Control of Telomeric Proteins. Mol. Cell. Biol. 2007, 27, 5898–5909.
  36. Liu, D.; O’Connor, M.S.; Qin, J.; Songyang, Z. Telosome, a Mammalian Telomere-associated Complex Formed by Multiple Telomeric Proteins. J. Biol. Chem. 2004, 279, 51338–51342.
  37. O’Connor, M.S.; Safari, A.; Xin, H.; Liu, D.; Songyang, Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc. Natl. Acad. Sci. USA 2006, 103, 11874–11879.
  38. Ye, J.Z.; de Lange, T. Tin2 is a tankyrase 1 parp modulator in the trf1 telomere length control complex. Nat. Genet. 2004, 36, 618–623.
  39. Li, J.S.Z.; Fusté, J.M.; Simavorian, T.; Bartocci, C.; Tsai, J.; Karlseder, J.; Denchi, E.L. TZAP: A telomere-associated protein involved in telomere length control. Science 2017, 355, 638–641.
  40. Marcand, S.; Gilson, E.; Shore, D. A Protein-Counting Mechanism for Telomere Length Regulation in Yeast. Science 1997, 275, 986–990.
  41. Patel, T.N.; Vasan, R.; Gupta, D.; Patel, J.; Trivedi, M. Shelterin Proteins and Cancer. Asian Pac. J. Cancer Prev. 2015, 16, 3085–3090.
  42. Palm, W.; de Lange, T. How shelterin protects mammalian telomeres. Annu. Rev. Genet. 2008, 42, 301–334.
  43. Xin, H.; Liu, D.; Songyang, Z. The telosome/shelterin complex and its functions. Genome Biol. 2008, 9, 232.
  44. Tejera, A.M.; Stagno d’Alcontres, M.; Thanasoula, M.; Marion, R.M.; Martinez, P.; Liao, C.; Flores, J.M.; Tarsounas, M.; Blasco, M.A. Tpp1 is required for tert recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice. Dev. Cell 2010, 18, 775–789.
  45. Gao, H.; Cervantes, R.B.; Mandell, E.K.; Otero, J.H.; Lundblad, V. RPA-like proteins mediate yeast telomere function. Nat. Struct. Mol. Biol. 2007, 14, 208–214.
  46. Wellinger, R.J. The CST Complex and Telomere Maintenance: The Exception Becomes the Rule. Mol. Cell 2009, 36, 168–169.
  47. Chen, L.-Y.; Lingner, J. CST for the grand finale of telomere replication. Nucleus 2013, 4, 277–282.
  48. Martín, V.; Du, L.-L.; Rozenzhak, S.; Russell, P. Protection of telomeres by a conserved Stn1 Ten1 complex. Proc. Natl. Acad. Sci. USA 2007, 104, 14038–14043.
  49. Chen, H.-W.; Xue, J.; Churikov, D.; Hass, E.P.; Shi, S.; Lemon, L.D.; Luciano, P.; Bertuch, A.A.; Zappulla, D.C.; Géli, V.; et al. Structural Insights into Yeast Telomerase Recruitment to Telomeres. Cell 2018, 172, 331–343.e13.
  50. Wold, M.S. Replication Protein A: A Heterotrimeric, Single-Stranded DNA-Binding Protein Required for Eukaryotic DNA Metabolism. Annu. Rev. Biochem. 1997, 66, 61–92.
  51. Lim, C.J.; Barbour, A.T.; Zaug, A.J.; Goodrich, K.J.; McKay, A.E.; Wuttke, D.S.; Cech, T.R. The structure of human CST reveals a decameric assembly bound to telomeric DNA. Science 2020, 368, 1081–1085.
  52. Miyake, Y.; Nakamura, M.; Nabetani, A.; Shimamura, S.; Tamura, M.; Yonehara, S.; Saito, M.; Ishikawa, F. RPA-like Mammalian Ctc1-Stn1-Ten1 Complex Binds to Single-Stranded DNA and Protects Telomeres Independently of the Pot1 Pathway. Mol. Cell 2009, 36, 193–206.
  53. Rice, C.; Skordalakes, E. Structure and function of the telomeric CST complex. Comput. Struct. Biotechnol. J. 2016, 14, 161–167.
  54. Chastain, M.; Zhou, Q.; Shiva, O.; Fadri-Moskwik, M.; Whitmore, L.; Jia, P.; Dai, X.; Huang, C.; Ye, P.; Chai, W. Human CST Facilitates Genome-wide RAD51 Recruitment to GC-Rich Repetitive Sequences in Response to Replication Stress. Cell Rep. 2016, 16, 1300–1314.
  55. Price, C.; Boltz, K.A.; Chaiken, M.F.; Stewart, J.A.; Beilstein, M.A.; Shippen, D.E. Evolution of CST function in telomere maintenance. Cell Cycle 2010, 9, 3177–3185.
  56. Stewart, J.A.; Wang, Y.; Ackerson, S.M.; Schuck, P.L. Emerging roles of cst in maintaining genome stability and human disease. Front. Biosci. 2018, 23, 1564–1586.
  57. Maréchal, A.; Zou, L. RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response. Cell Res. 2015, 25, 9–23.
  58. Stewart, J.A.; Wang, F.; Chaiken, M.F.; Kasbek, C.; Chastain, P.D., 2nd; Wright, W.E.; Price, C.M. Human CST promotes telomere duplex replication and general replication restart after fork stalling. EMBO J. 2012, 31, 3537–3549.
  59. Fanning, E.; Klimovich, V.; Nager, A.R. A dynamic model for replication protein A (RPA) function in DNA processing pathways. Nucleic Acids Res. 2006, 34, 4126–4137.
  60. Gu, P.; Jia, S.; Takasugi, T.; Smith, E.; Nandakumar, J.; Hendrickson, E.; Chang, S. CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length. Aging Cell 2018, 17, e12783.
  61. Gu, P.; Min, J.-N.; Wang, Y.; Huang, C.; Peng, T.; Chai, W.; Chang, S. CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. EMBO J. 2012, 31, 2309–2321.
  62. Hom, R.A.; Wuttke, D.S. Human CST Prefers G-Rich but Not Necessarily Telomeric Sequences. Biochemistry 2017, 56, 4210–4218.
  63. Huang, C.; Dai, X.; Chai, W. Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in. Cell Res. 2012, 22, 1681–1695.
  64. Huang, C.; Jia, P.; Chastain, M.; Shiva, O.; Chai, W. The human ctc1/stn1/ten1 complex regulates telomere maintenance in alt cancer cells. Exp. Cell Res. 2017, 355, 95–104.
  65. Feng, X.; Hsu, S.-J.; Bhattacharjee, A.; Wang, Y.; Diao, J.; Price, C.M. CTC1-STN1 terminates telomerase while STN1-TEN1 enables C-strand synthesis during telomere replication in colon cancer cells. Nat. Commun. 2018, 9, 2827.
  66. Bhattacharjee, A.; Wang, Y.; Diao, J.; Price, C.M. Dynamic DNA binding, junction recognition and G4 melting activity underlie the telomeric and genome-wide roles of human CST. Nucleic Acids Res. 2017, 45, 12311–12324.
  67. Boltz, K.A.; Leehy, K.; Song, X.; Nelson, A.; Shippen, D.E. ATR cooperates with CTC1 and STN1 to maintain telomeres and genome integrity in Arabidopsis. Mol. Biol. Cell 2012, 23, 1558–1568.
  68. Casteel, D.E.; Zhuang, S.; Zeng, Y.; Perrino, F.W.; Boss, G.R.; Goulian, M.; Pilz, R.B. A DNA polymerase-α·primase cofactor with homology to replication protein a-32 regulates DNA replication in mammalian cells. J. Biol. Chem. 2009, 284, 5807–5818.
  69. Ganduri, S.; Lue, N.F. STN1–POLA2 interaction provides a basis for primase-pol α stimulation by human STN1. Nucleic Acids Res. 2017, 45, 9455–9466.
  70. Wang, F.; Stewart, J.A.; Kasbek, C.; Zhao, Y.; Wright, W.E.; Price, C.M. Human CST Has Independent Functions during Telomere Duplex Replication and C-Strand Fill-In. Cell Rep. 2012, 2, 1096–1103.
  71. Chen, L.-Y.; Redon, S.; Lingner, J. The human CST complex is a terminator of telomerase activity. Nature 2012, 488, 540–544.
  72. Wang, Y.; Brady, K.S.; Caiello, B.P.; Ackerson, S.M.; Stewart, J.A. Human cst suppresses origin licensing and promotes and-1/ctf4 chromatin association. Life Sci. Alliance 2019, 2.
  73. Li, Y.; Xiao, H.; de Renty, C.; Jaramillo-Lambert, A.; Han, Z.; DePamphilis, M.L.; Brown, K.; Zhu, W. The Involvement of Acidic Nucleoplasmic DNA-binding Protein (And-1) in the Regulation of Prereplicative Complex (pre-RC) Assembly in Human Cells. J. Biol. Chem. 2012, 287, 42469–42479.
  74. Feng, X.; Hsu, S.-J.; Kasbek, C.; Chaiken, M.; Price, C.M. CTC1-mediated C-strand fill-in is an essential step in telomere length maintenance. Nucleic Acids Res. 2017, 45, 4281–4293.
  75. Wu, P.; Takai, H.; de Lange, T. Telomeric 3′ Overhangs Derive from Resection by Exo1 and Apollo and Fill-In by POT1b-Associated CST. Cell 2012, 150, 39–52.
  76. Feng, S.; Zhao, Y.; Xu, Y.; Ning, S.; Huo, W.; Hou, M.; Gao, G.; Ji, J.; Guo, R.; Xu, D. Ewing Tumor-associated Antigen 1 Interacts with Replication Protein A to Promote Restart of Stalled Replication Forks. J. Biol. Chem. 2016, 291, 21956–21962.
  77. Zeman, M.K.; Cimprich, K.A. Causes and consequences of replication stress. Nat. Cell Biol. 2014, 16, 2–9.
  78. Cimprich, K.A.; Cortez, D. ATR: An essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 2008, 9, 616–627.
  79. Patil, M.; Pabla, N.; Dong, Z. Checkpoint kinase 1 in DNA damage response and cell cycle regulation. Cell. Mol. Life Sci. 2013, 70, 4009–4021.
  80. Cunniff, C.; Bassetti, J.A.; Ellis, N.A. Bloom’s syndrome: Clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol. Syndromol. 2017, 8, 4–23.
  81. Guler, G.D.; Liu, H.; Vaithiyalingam, S.; Arnett, D.R.; Kremmer, E.; Chazin, W.J.; Fanning, E. Human DNA Helicase B (HDHB) Binds to Replication Protein A and Facilitates Cellular Recovery from Replication Stress. J. Biol. Chem. 2012, 287, 6469–6481.
  82. Lee, M.; Shin, S.; Uhm, H.; Hong, H.; Kirk, J.; Hyun, K.; Kulikowicz, T.; Kim, J.; Ahn, B.; Bohr, V.A.; et al. Multiple RPAs make WRN syndrome protein a superhelicase. Nucleic Acids Res. 2018, 46, 4689–4698.
  83. Qin, Z.; Bi, L.; Hou, X.-M.; Zhang, S.; Zhang, X.; Lu, Y.; Li, M.; Modesti, M.; Xi, X.-G.; Sun, B. Human RPA activates BLM’s bidirectional DNA unwinding from a nick. eLife 2020, 9, 9.
  84. Bhat, K.; Bétous, R.; Cortez, D. High-affinity DNA-binding Domains of Replication Protein A (RPA) Direct SMARCAL1-dependent Replication Fork Remodeling. J. Biol. Chem. 2015, 290, 4110–4117.
  85. Martínez-Jiménez, M.I.; Lahera, A.; Blanco, L. Human PrimPol activity is enhanced by RPA. Sci. Rep. 2017, 7, 783.
  86. Garvik, B.; Carson, M.; Hartwell, L. Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Mol. Cell. Biol. 1995, 15, 6128–6138.
  87. Bryan, C.; Rice, C.; Harkisheimer, M.; Schultz, D.C.; Skordalakes, E. Structure of the Human Telomeric Stn1-Ten1 Capping Complex. PLoS ONE 2013, 8, e66756.
  88. Hughes, T.R.; Weilbaecher, R.G.; Walterscheid, M.; Lundblad, V. Identification of the single-strand telomeric DNA binding domain of the Saccharomyces cerevisiae Cdc13 protein. Proc. Natl. Acad. Sci. USA 2000, 97, 6457–6462.
  89. Lewis, K.A.; Pfaff, D.A.; Earley, J.N.; Altschuler, S.E.; Wuttke, D.S. The tenacious recognition of yeast telomere sequence by Cdc13 is fully exerted by a single OB-fold domain. Nucleic Acids Res. 2014, 42, 475–484.
  90. Sun, J.; Yang, Y.; Wan, K.; Mao, N.; Yu, T.-Y.; Lin, Y.-C.; DeZwaan, D.C.; Freeman, B.C.; Lin, J.-J.; Lue, N.F.; et al. Structural bases of dimerization of yeast telomere protein Cdc13 and its interaction with the catalytic subunit of DNA polymerase α. Cell Res. 2010, 21, 258–274.
  91. Ge, Y.; Wu, Z.; Chen, H.; Zhong, Q.; Shi, S.; Li, G.; Wu, J.; Lei, M. Structural insights into telomere protection and homeostasis regulation by yeast CST complex. Nat. Struct. Mol. Biol. 2020, 27, 752–762.
  92. Bochkareva, E.; Korolev, S.; Lees-Miller, S.P.; Bochkarev, A. Structure of the RPA trimerization core and its role in the multistep DNA-binding mechanism of RPA. EMBO J. 2002, 21, 1855–1863.
  93. Li, S.; Makovets, S.; Matsuguchi, T.; Blethrow, J.D.; Shokat, K.M.; Blackburn, E.H. Cdk1-Dependent Phosphorylation of Cdc13 Coordinates Telomere Elongation during Cell-Cycle Progression. Cell 2009, 136, 50–61.
  94. Liu, C.-C.; Gopalakrishnan, V.; Poon, L.-F.; Yan, T.; Li, S. Cdk1 Regulates the Temporal Recruitment of Telomerase and Cdc13-Stn1-Ten1 Complex for Telomere Replication. Mol. Cell. Biol. 2014, 34, 57–70.
  95. Tseng, S.-F.; Shen, Z.-J.; Tsai, H.-J.; Lin, Y.-H.; Teng, S.-C. Rapid Cdc13 turnover and telomere length homeostasis are controlled by Cdk1-mediated phosphorylation of Cdc13. Nucleic Acids Res. 2009, 37, 3602–3611.
  96. Wu, Y.; DiMaggio, P.A., Jr.; Perlman, D.H.; Zakian, V.A.; Garcia, B.A. Novel Phosphorylation Sites in the S. cerevisiae Cdc13 Protein Reveal New Targets for Telomere Length Regulation. J. Proteome Res. 2013, 12, 316–327.
  97. Zhang, W.; Durocher, D. De novo telomere formation is suppressed by the Mec1-dependent inhibition of Cdc13 accumulation at DNA breaks. Genes Dev. 2010, 24, 502–515.
  98. Poncet, D.; Belleville, A.; de Roodenbeke, C.T.; de Climens, A.R.; Ben Simon, E.; Merle-Beral, H.; Callet-Bauchu, E.; Salles, G.; Sabatier, L.; Delic, J.; et al. Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia. Blood 2008, 111, 2388–2391.
  99. Chandra, A.; Hughes, T.R.; Nugent, C.I.; Lundblad, V. Cdc13 both positively and negatively regulates telomere replication. Genes Dev. 2001, 15, 404–414.
  100. Evans, S.K.; Lundblad, V. Positive and negative regulation of telomerase access to the telomere. J. Cell Sci. 2000, 113, 3357–3364.
  101. Zhong, F.; Batista, L.; Freund, A.; Pech, M.F.; Venteicher, A.; Artandi, S.E. TPP1 OB-Fold Domain Controls Telomere Maintenance by Recruiting Telomerase to Chromosome Ends. Cell 2012, 150, 481–494.
  102. Giraud-Panis, M.-J.; Teixeira, M.T.; Géli, V.; Gilson, E. CST Meets Shelterin to Keep Telomeres in Check. Mol. Cell 2010, 39, 665–676.
  103. Langston, R.E.; Palazzola, D.; Bonnell, E.; Wellinger, R.J.; Weinert, T. Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping. PLoS Genet. 2020, 16, e1008733.
  104. Han, E.; Patel, N.A.; Yannuzzi, N.A.; Laura, D.M.; Fan, K.C.; Negron, C.I.; Prakhunhungsit, S.; Thorson, W.L.; Berrocal, A.M. A unique case of coats plus syndrome and dyskeratosis congenita in a patient with CTC1 mutations. Ophthalmic Genet. 2020, 41, 363–367.
  105. Bs, R.B.K.; Bs, K.E.G.; Usmani, G.N.; Asdourian, G.K.; Williams, D.A.; Hofmann, I.; Agarwal, S. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr. Blood Cancer 2012, 59, 311–314.
  106. Dai, X.; Huang, C.; Bhusari, A.; Sampathi, S.; Schubert, K.; Chai, W. Molecular steps of G-overhang generation at human telomeres and its function in chromosome end protection. EMBO J. 2010, 29, 2788–2801.
  107. Wang, Y.; Chai, W. Pathogenic CTC1 mutations cause global genome instabilities under replication stress. Nucleic Acids Res. 2018, 46, 3981–3992.
  108. Goulian, M.; Heard, C.J. The mechanism of action of an accessory protein for DNA polymerase alpha/primase. J. Biol. Chem. 1990, 265, 13231–13239.
  109. Grossi, S.; Puglisi, A.; Dmitriev, P.V.; Lopes, M.; Shore, D. Pol12, the B subunit of DNA polymerase α, functions in both telomere capping and length regulation. Genes Dev. 2004, 18, 992–1006.
  110. Petreaca, R.C.; Chiu, H.-C.; Eckelhoefer, H.A.; Chuang, C.; Xu, L.; Nugent, C.I. Chromosome end protection plasticity revealed by Stn1p and Ten1p bypass of Cdc13p. Nat. Cell Biol. 2006, 8, 748–755.
  111. Pennock, E.; Buckley, K.; Lundblad, V. Cdc13 Delivers Separate Complexes to the Telomere for End Protection and Replication. Cell 2001, 104, 387–396.
  112. Qian, W.; Wang, J.; Jin, N.-N.; Fu, X.-H.; Lin, Y.-C.; Lin, J.-J.; Zhou, J.-Q. Ten1p promotes the telomeric DNA-binding activity of Cdc13p: Implication for its function in telomere length regulation. Cell Res. 2009, 19, 849–863.
  113. Wang, F.; Stewart, J.; Price, C.M. Human cst abundance determines recovery from diverse forms of DNA damage and replication stress. Cell Cycle 2014, 13, 3488–3498.
  114. Bagcchi, S. POT1: A genetic link for familial glioma. Lancet Oncol. 2015, 16, e12.
  115. Robles-Espinoza, C.D.; Harland, M.; Ramsay, A.J.; Aoude, L.G.; Quesada, V.; Ding, Z.; Pooley, K.A.; Pritchard, A.L.; Tiffen, J.C.; Petljak, M.; et al. POT1 loss-of-function variants predispose to familial melanoma. Nat. Genet. 2014, 46, 478–481.
  116. Ramsay, A.J.; Quesada, V.; Foronda, M.; Conde, L.; Martínez-Trillos, A.; Villamor, N.; Rodríguez, D.; Kwarciak, A.; Garabaya, C.; Gallardo, M.; et al. POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nat. Genet. 2013, 45, 526–530.
  117. Calvete, O.; Martinez, P.; Garcia-Pavia, P.; Benitez-Buelga, C.; Paumard-Hernandez, B.; Fernandez, V.; Dominguez, F.; Salas, C.; Romero-Laorden, N.; Garcia-Donas, J.; et al. A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li–Fraumeni-like families. Nat. Commun. 2015, 6, 8383.
  118. Shen, J.; Gammon, M.D.; Wu, H.-C.; Terry, M.B.; Wang, Q.; Bradshaw, P.T.; Teitelbaum, S.L.; Neugut, A.I.; Santella, R.M. Multiple Genetic Variants in Telomere Pathway Genes and Breast Cancer Risk. Cancer Epidemiol. Biomark. Prev. 2010, 19, 219–228.
  119. Richard, M.A.; Lupo, P.J.; Morton, L.M.; Yasui, Y.A.; Sapkota, Y.A.; Arnold, M.A.; Aubert, G.; Neglia, J.P.; Turcotte, L.M.; Leisenring, W.M.; et al. Genetic variation in POT1 and risk of thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study. PLoS ONE 2020, 15, e0228887.
  120. Hiyama, E.; Hiyama, K. Telomere and telomerase in stem cells. Br. J. Cancer 2007, 96, 1020–1024.
  121. Lucibello, F.; Menegatti, S.; Menger, L. Methods to edit T cells for cancer immunotherapy. Methods Enzymol. 2020, 631, 107–135.
  122. Borah, S.; Xi, L.; Zaug, A.J.; Powell, N.M.; Dancik, G.M.; Cohen, S.B.; Costello, J.C.; Theodorescu, D.; Cech, T.R. TERTpromoter mutations and telomerase reactivation in urothelial cancer. Science 2015, 347, 1006–1010.
  123. Inderberg-Suso, E.-M.; Trachsel, S.; Lislerud, K.; Rasmussen, A.-M.; Gaudernack, G. Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. OncoImmunology 2012, 1, 670–686.
  124. Brunsvig, P.F.; Aamdal, S.; Gjertsen, M.K.; Kvalheim, G.; Markowski-Grimsrud, C.J.; Sve, I.; Dyrhaug, M.; Trachsel, S.; Møller, M.; Eriksen, J.A.; et al. Telomerase peptide vaccination: A phase I/II study in patients with non-small cell lung cancer. Cancer Immunol. Immunother. 2006, 55, 1553–1564.
  125. Greten, T.F.; Forner, A.; Korangy, F.; N’Kontchou, G.; Barget, N.; Ayuso, C.; Ormandy, L.A.; Manns, M.P.; Beaugrand, M.; Bruix, J. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer 2010, 10, 209.
  126. Hunger, R.E.; Lang, K.K.; Markowski, C.J.; Trachsel, S.; Møller, M.; Eriksen, J.A.; Rasmussen, A.-M.; Braathen, L.R.; Gaudernack, G. Vaccination of patients with cutaneous melanoma with telomerase-specific peptides. Cancer Immunol. Immunother. 2011, 60, 1553–1564.
  127. Kyte, J.A.; Gaudernack, G.; Dueland, S.; Trachsel, S.; Julsrud, L.; Aamdal, S. Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients. Clin. Cancer Res. 2011, 17, 4568–4580.
  128. Middleton, G.; Silcocks, P.; Cox, T.; Valle, J.; Wadsley, J.; Propper, D.; Coxon, F.; Ross, P.; Madhusudan, S.; Roques, T.; et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): An open-label, randomised, phase 3 trial. Lancet Oncol. 2014, 15, 829–840.
  129. Mizukoshi, E.; Kaneko, S. Telomerase-Targeted Cancer Immunotherapy. Int. J. Mol. Sci. 2019, 20, 1823.
  130. Staff, C.; Mozaffari, F.; Frodin, J.-E.; Mellstedt, H.; Liljefors, M.G. Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients. Int. J. Oncol. 2014, 45, 1293–1303.
  131. Khong, H.; Overwijk, W.W. Adjuvants for peptide-based cancer vaccines. J. Immunother. Cancer 2016, 4, 56.
  132. Kim, B.-K.; Kim, B.-R.; Lee, H.-J.; Lee, S.-A.; Kim, B.-J.; Kim, H.; Won, Y.-S.; Shon, W.-J.; Lee, N.-R.; Inn, K.-S.; et al. Tumor-suppressive effect of a telomerase-derived peptide by inhibiting hypoxia-induced HIF-1α-VEGF signaling axis. Biomaterials 2014, 35, 2924–2933.
  133. Kim, C.; Lee, S.G.; Yang, W.M.; Arfuso, F.; Um, J.Y.; Kumar, A.P.; Bian, J.; Sethi, G.; Ahn, K.S. Formononetin-induced oxidative stress abrogates the activation of stat3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model. Cancer Lett. 2018, 431, 123–141.
  134. Kim, G.E.; Jung, A.R.; Kim, M.Y.; Lee, J.B.; Im, J.H.; Lee, K.W.; Park, Y.H.; Lee, J.Y. GV1001 Induces Apoptosis by Reducing Angiogenesis in Renal Cell Carcinoma Cells Both In Vitro and In Vivo. Urology 2018, 113, 129–137.
  135. Park, Y.H.; Jung, A.R.; Kim, G.E.; Kim, M.Y.; Sung, J.W.; Shin, D.; Cho, H.J.; Ha, U.S.; Hong, S.H.; Kim, S.W.; et al. Gv1001 inhibits cell viability and induces apoptosis in castration-resistant prostate cancer cells through the akt/nf-kappab/vegf pathway. J. Cancer 2019, 10, 6269–6277.
  136. Kim, H.; Seo, E.-H.; Lee, S.-H.; Kim, B.-J. The Telomerase-Derived Anticancer Peptide Vaccine GV1001 as an Extracellular Heat Shock Protein-Mediated Cell-Penetrating Peptide. Int. J. Mol. Sci. 2016, 17, 2054.
  137. Schlapbach, C.; Yerly, D.; Daubner, B.; Yawalkar, N.; Hunger, R.E. Telomerase-specific GV1001 peptide vaccination fails to induce objective tumor response in patients with cutaneous T cell lymphoma. J. Dermatol. Sci. 2011, 62, 75–83.
  138. Fenoglio, D.; Traverso, P.; Parodi, A.; Tomasello, L.; Negrini, S.; Kalli, F.; Battaglia, F.; Ferrera, F.; Sciallero, M.S.; Murdaca, G.; et al. A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer. Cancer Immunol. Immunother. 2013, 62, 1041–1052.
  139. Aucouturier, J.; Dupuis, L.; Deville, S.; Ascarateil, S.; Ganne, V. Montanide ISA 720 and 51: A new generation of water in oil emulsions as adjuvants for human vaccines. Expert Rev. Vaccines 2002, 1, 111–118.
  140. Johnston, D.; Bystryn, J.-C. Topical imiquimod is a potent adjuvant to a weakly-immunogenic protein prototype vaccine. Vaccine 2006, 24, 1958–1965.
  141. Fenoglio, D.; Parodi, A.; Lavieri, R.; Kalli, F.; Ferrera, F.; Tagliamacco, A.; Guastalla, A.; Lamperti, M.G.; Giacomini, M.; Filaci, G. Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one. Hum. Vaccines Immunother. 2015, 11, 838–850.
  142. Filaci, G.; Fenoglio, D.; Nolè, F.; Zanardi, E.; Tomasello, L.; Aglietta, M.; Del Conte, G.; Carles, J.; Morales-Barrera, R.; Guglielmini, P.; et al. Telomerase-based GX301 cancer vaccine in patients with metastatic castration-resistant prostate cancer: A randomized phase II trial. Cancer Immunol. Immunother. 2021, 70, 1–14.
  143. Van der Burg, S.H. Correlates of immune and clinical activity of novel cancer vaccines. Semin. Immunol. 2018, 39, 119–136.
  144. Ellingsen, E.B.; Aamdal, E.; Inderberg, E.M.; Rasch, W.; Brunsvig, P.; Aamdal, S.; Hovig, E.; Nyakas, M.; Guren, T.K.; Gaudernack, G. A phase I/IIa clinical trial investigating the therapeutic cancer vaccine UV1 in combination with ipilimumab in patients with malignant melanoma: Four-year survival update. J. Clin. Oncol. 2020, 38, 62.
  145. Haakensen, V.D.; Nowak, A.K.; Ellingsen, E.B.; Farooqi, S.J.; Bjaanæs, M.M.; Horndalsveen, H.; Mcculloch, T.; Grundberg, O.; Cedres, S.M.; Helland, Å. NIPU: A randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma. J. Transl. Med. 2021, 19, 1–9.
  146. Zakharia, Y.; O’Day, S.; Rasch, W.; Milhem, M.M. A phase I clinical trial investigating the telomerase vaccine UV1 in combination with pembrolizumab in patients with advanced melanoma. J. Clin. Oncol. 2021, 39, 2620.
  147. Vetsika, E.-K.; Papadimitraki, E.; Aggouraki, D.; Konsolakis, G.; Mela, M.-E.; Kotsakis, A.; Christou, S.; Patramani, S.; Alefantinou, M.; Kaskara, A.; et al. Sequential Administration of the Native TERT572 Cryptic Peptide Enhances the Immune Response Initiated by its Optimized Variant TERT572Y in Cancer Patients. J. Immunother. 2011, 34, 641–650.
  148. Bolonaki, I.; Kotsakis, A.; Papadimitraki, E.; Aggouraki, D.; Konsolakis, G.; Vagia, A.; Christophylakis, C.; Nikoloudi, I.; Magganas, E.; Galanis, A.; et al. Vaccination of Patients with Advanced Non–Small-Cell Lung Cancer With an Optimized Cryptic Human Telomerase Reverse Transcriptase Peptide. J. Clin. Oncol. 2007, 25, 2727–2734.
  149. Kotsakis, A.; Papadimitraki, E.; Vetsika, E.K.; Aggouraki, D.; Dermitzaki, E.K.; Hatzidaki, D.; Kentepozidis, N.; Mavroudis, D.; Georgoulias, V. A phase II trial evaluating the clinical and immunologic response of HLA-A2+ non-small cell lung cancer patients vaccinated with an hTERT cryptic peptide. Lung Cancer 2014, 86, 59–66.
  150. Kotsakis, A.; Vetsika, E.-K.; Christou, S.; Hatzidaki, D.; Vardakis, N.; Aggouraki, D.; Konsolakis, G.; Georgoulias, V.; Christophyllakis, C.; Cordopatis, P.; et al. Clinical outcome of patients with various advanced cancer types vaccinated with an optimized cryptic human telomerase reverse transcriptase (TERT) peptide: Results of an expanded phase II study. Ann. Oncol. 2012, 23, 442–449.
  151. Vetsika, E.-K.; Konsolakis, G.; Aggouraki, D.; Kotsakis, A.; Papadimitraki, E.; Christou, S.; Menez-Jamet, J.; Kosmatopoulos, K.; Georgoulias, V.; Mavroudis, D. Immunological responses in cancer patients after vaccination with the therapeutic telomerase-specific vaccine Vx-001. Cancer Immunol. Immunother. 2012, 61, 157–168.
  152. Brower, V. Telomerase-Based Therapies Emerging Slowly. J. Natl. Cancer Inst. 2010, 102, 520–521.
  153. Ruden, M.; Puri, N. Novel anticancer therapeutics targeting telomerase. Cancer Treat. Rev. 2013, 39, 444–456.
  154. Salazar-Onfray, F.; Pereda, C.; Reyes, D.; López, M.N. TAPCells, the Chilean dendritic cell vaccine against melanoma and prostate cancer. Biol. Res. 2013, 46, 431–440.
  155. Yan, J.; Pankhong, P.; Shin, T.H.; Obeng-Adjei, N.; Morrow, M.P.; Walters, J.N.; Khan, A.S.; Sardesai, N.; Weiner, D.B. Highly Optimized DNA Vaccine Targeting Human Telomerase Reverse Transcriptase Stimulates Potent Antitumor Immunity. Cancer Immunol. Res. 2013, 1, 179–189.
  156. Thalmensi, J.; Pliquet, E.; Liard, C.; Escande, M.; Bestetti, T.; Julithe, M.; Kostrzak, A.; Pailhes-Jimenez, A.-S.; Bourges, E.; Loustau, M.; et al. Anticancer DNA vaccine based on human telomerase reverse transcriptase generates a strong and specific T cell immune response. OncoImmunology 2016, 5, e1083670.
  157. Aurisicchio, L.; Fridman, A.; Mauro, D.; Sheloditna, R.; Chiappori, A.; Bagchi, A.; Ciliberto, G. Safety, tolerability and immunogenicity of v934/v935 htert vaccination in cancer patients with selected solid tumors: A phase I study. J. Transl. Med. 2020, 18, 39.
  158. Gangat, A.A.; Te, I.; Kao, Y.-J. Steady States of Infinite-Size Dissipative Quantum Chains via Imaginary Time Evolution. Phys. Rev. Lett. 2017, 119, 010501.
  159. Kageyama, S.; Ikeda, H.; Miyahara, Y.; Imai, N.; Ishihara, M.; Saito, K.; Sugino, S.; Ueda, S.; Ishikawa, T.; Kokura, S.; et al. Adoptive Transfer of MAGE-A4 T-cell Receptor Gene-Transduced Lymphocytes in Patients with Recurrent Esophageal Cancer. Clin. Cancer Res. 2015, 21, 2268–2277.
  160. Jackson, H.J.; Rafiq, S.; Brentjens, R.J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 2016, 13, 370–383.
  161. Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544.
  162. Bejarano, L.; Bosso, G.; Louzame, J.; Serrano, R.; Gómez-Casero, E.; Martinez-Torrecuadrada, J.L.; Martínez, S.; Blanco-Aparicio, C.; Pastor, J.; Blasco, M.A. Multiple cancer pathways regulate telomere protection. EMBO Mol. Med. 2019, 11, 10292.
  163. Mu, X.; Sang, Y.; Fang, C.; Shao, B.; Yang, L.; Yao, K.; Zhao, X.; Gou, J.; Wei, Y.; Yi, T.; et al. Immunotherapy of tumors with human telomerase reverse transcriptase immortalized human umbilical vein endothelial cells. Int. J. Oncol. 2015, 47, 1901–1911.
  164. Cesare, A.; Reddel, R. Alternative lengthening of telomeres: Models, mechanisms and implications. Nat. Rev. Genet. 2010, 11, 319–330.
  165. Slatter, T.L.; Tan, X.; Yuen, Y.C.; Gunningham, S.; Ma, S.S.; Daly, E.; Packer, S.; Devenish, C.; Royds, J.A.; Hung, N.A. The alternative lengthening of telomeres pathway may operate in non-neoplastic human cells. J. Pathol. 2011, 226, 509–518.
  166. Dilley, R.L.; Greenberg, R.A. ALTernative Telomere Maintenance and Cancer. Trends Cancer 2015, 1, 145–156.
  167. Fan, H.-C.; Chen, C.-M.; Chi, C.-S.; Tsai, J.-D.; Chiang, K.-L.; Chang, Y.-K.; Lin, S.-Z.; Harn, H.-J. Targeting Telomerase and ATRX/DAXX Inducing Tumor Senescence and Apoptosis in the Malignant Glioma. Int. J. Mol. Sci. 2019, 20, 200.
  168. Sommer, A.; Royle, N.J. ALT: A Multi-Faceted Phenomenon. Genes 2020, 11, 133.
  169. Dyer, M.A.; Qadeer, Z.; Valle-Garcia, D.; Bernstein, E. ATRX and DAXX: Mechanisms and Mutations. Cold Spring Harb. Perspect. Med. 2017, 7, a026567.
  170. Yang, X.; Khosravi-Far, R.; Chang, H.Y.; Baltimore, D. Daxx, a Novel Fas-Binding Protein That Activates JNK and Apoptosis. Cell 1997, 89, 1067–1076.
  171. Gibbons, R.J.; McDowell, T.L.; Raman, S.; O’Rourke, D.M.; Garrick, D.; Ayyub, H.; Higgs, D.R. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat. Genet. 2000, 24, 368–371.
  172. Gibbons, R. Alpha thalassaemia-mental retardation, X linked. Orphanet J. Rare Dis. 2006, 1, 15.
  173. Brosnan-Cashman, J.A.; Yuan, M.; Graham, M.K.; Rizzo, A.J.; Myers, K.M.; Davis, C.; Zhang, R.; Esopi, D.M.; Raabe, E.H.; Eberhart, C.G.; et al. ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner. PLoS ONE 2018, 13, e0204159.
  174. Ro, C.; Chai, W.; Yu, V.E.; Yu, R. Pancreatic neuroendocrine tumors: Biology, diagnosis, and treatment. Chin. J. Cancer 2013, 32, 312–324.
  175. Jiao, Y.; Shi, C.; Edil, B.H.; de Wilde, R.F.; Klimstra, D.S.; Maitra, A.; Schulick, R.D.; Tang, L.H.; Wolfgang, C.L.; Choti, M.A.; et al. DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors. Science 2011, 331, 1199–1203.
  176. Heaphy, C.M.; de Wilde, R.F.; Jiao, Y.; Klein, A.P.; Edil, B.H.; Shi, C.; Bettegowda, C.; Rodriguez, F.J.; Eberhart, C.G.; Hebbar, S.; et al. Altered Telomeres in Tumors with ATRX and DAXX Mutations. Science 2011, 333, 425.
  177. Pekmezci, M.; Rice, T.; Molinaro, A.M.; Walsh, K.; Decker, P.A.; Hansen, H.; Sicotte, H.; Kollmeyer, T.M.; McCoy, L.S.; Sarkar, G.; et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: Additional prognostic roles of ATRX and TERT. Acta Neuropathol. 2017, 133, 1001–1016.
  178. Clynes, D.; Higgs, D.; Gibbons, R. The chromatin remodeller ATRX: A repeat offender in human disease. Trends Biochem. Sci. 2013, 38, 461–466.
  179. Napier, C.E.; Huschtscha, L.I.; Harvey, A.; Bower, K.; Noble, J.R.; Hendrickson, E.A.; Reddel, R.R. ATRX represses alternative lengthening of telomeres. Oncotarget 2015, 6, 16543–16558.
  180. Killela, P.J.; Reitman, Z.J.; Jiao, Y.; Bettegowda, C.; Agrawal, N.; Diaz, L.A., Jr.; Friedman, A.H.; Friedman, H.; Gallia, G.L.; Giovanella, B.C.; et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl. Acad. Sci. USA 2013, 110, 6021–6026.
  181. Flynn, R.L.; Cox, K.E.; Jeitany, M.; Wakimoto, H.; Bryll, A.R.; Ganem, N.J.; Bersani, F.; Pineda, J.R.; Suvà, M.L.; Benes, C.H.; et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 2015, 347, 273–277.
  182. Shay, J.W.; Reddel, R.R.; Wright, W.E. Cancer and Telomeres—An ALTernative to Telomerase. Science 2012, 336, 1388–1390.
  183. Kosiol, N.; Juranek, S.; Brossart, P.; Heine, A.; Paeschke, K. G-quadruplexes: A promising target for cancer therapy. Mol. Cancer 2021, 20, 1–18.
  184. Chhabra, G.; Wojdyla, L.; Frakes, M.; Schrank, Z.; Leviskas, B.; Ivancich, M.; Vinay, P.; Ganapathy, R.; Ramirez, B.E.; Puri, N. Mechanism of Action of G-Quadruplex–Forming Oligonucleotide Homologous to the Telomere Overhang in Melanoma. J. Investig. Dermatol. 2018, 138, 903–910.
  185. Mender, I.; Gryaznov, S.; Dikmen, Z.G.; Wright, W.E.; Shay, J.W. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. Cancer Discov. 2014, 5, 82–95.
  186. Naderlinger, E.; Holzmann, K. Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas. Genes 2017, 8, 145.
  187. Dogan, F.; Forsyth, N. Telomerase Regulation: A Role for Epigenetics. Cancers 2021, 13, 1213.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Biochemistry & Molecular Biology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Hueng-Chuen Fan
View Times: 755
Revision: 1 time (View History)
Update Date: 23 Mar 2022
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback