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Lokanathan, Y. DNA Damage Response (DDR). Encyclopedia. Available online: https://encyclopedia.pub/entry/14595 (accessed on 18 November 2024).
Lokanathan Y. DNA Damage Response (DDR). Encyclopedia. Available at: https://encyclopedia.pub/entry/14595. Accessed November 18, 2024.
Lokanathan, Yogeswaran. "DNA Damage Response (DDR)" Encyclopedia, https://encyclopedia.pub/entry/14595 (accessed November 18, 2024).
Lokanathan, Y. (2021, September 27). DNA Damage Response (DDR). In Encyclopedia. https://encyclopedia.pub/entry/14595
Lokanathan, Yogeswaran. "DNA Damage Response (DDR)." Encyclopedia. Web. 27 September, 2021.
DNA Damage Response (DDR)
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22189900

DNA damage could occur in cells either endogenously, through normal cellular replication and metabolism, or exogenously through ultraviolet (UV), ionizing radiation (IR) or various genotoxic compounds] that could induce DNA damage. Different stressors will cause different types of DNA damage. Normal DNA replication could induce mismatch of the nucleotide and cause mutations. Stressors such as oxidative stress will produce reactive oxygen species (ROS) from normal cellular metabolism or from external genotoxic compound, which will cause DNA breaks, either single-stranded or double-stranded. Unrepaired DNA damage could cause severe mutations and chromosomal instability, which would have detrimental effects on the cells and lead to cell death, while DNA breaks that are repaired through non-homologous end joining (NHEJ) might cause mutations during the process.
The DDR is the response mechanism which will detect any DNA damage that occurs throughout the chromosome and will activate a repair cascade to the damage site. This will help the cells either to proliferate normally if the repair was successful or to activate the cellular programmed cell death if the damage was too extensive and was unable to be repaired. The known DNA damage repair mechanisms include mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end joining (NHEJ). Specific types of DNA damage could be fixed by a specific repair factor, such as the ATM kinase, which is the main factor in double-strand break repair through NHEJ. Figure 1 shows the causes and types of DNA damage as well as the response cascade involved in repairing the damages.

TRF2 DNA damage response telomeres protection extra-telomeric

1. DNA Damage Response (DDR)

DNA damage could occur in cells either endogenously, through normal cellular replication [1][2] and metabolism [3][4], or exogenously through ultraviolet (UV) [5][6], ionizing radiation (IR) [7][8] or various genotoxic compounds [9][10] that could induce DNA damage. Different stressors will cause different types of DNA damage. Normal DNA replication could induce mismatch of the nucleotide and cause mutations [11][12][13][14]. Stressors such as oxidative stress will produce reactive oxygen species (ROS) from normal cellular metabolism or from external genotoxic compound [15][16][17], which will cause DNA breaks, either single-stranded or double-stranded [18][19][20]. Unrepaired DNA damage could cause severe mutations and chromosomal instability, which would have detrimental effects on the cells and lead to cell death, while DNA breaks that are repaired through non-homologous end joining (NHEJ) might cause mutations during the process.
The DDR is the response mechanism which will detect any DNA damage that occurs throughout the chromosome and will activate a repair cascade to the damage site. This will help the cells either to proliferate normally if the repair was successful or to activate the cellular programmed cell death if the damage was too extensive and was unable to be repaired. The known DNA damage repair mechanisms include mismatch repair (MMR) [21], base excision repair (BER) [22], nucleotide excision repair (NER) [23], homologous recombination (HR) [24] and non-homologous end joining (NHEJ) [25]. Specific types of DNA damage could be fixed by a specific repair factor, such as the ATM kinase, which is the main factor in double-strand break repair through NHEJ [26]. Figure 1 shows the causes and types of DNA damage as well as the response cascade involved in repairing the damages.
Ijms 22 09900 g001 550
Figure 1. DNA damage and repair mechanisms. The figure illustrates the common DNA damaging agents (top), the types of DNA damage caused by these agents (middle) and the known response and repair mechanisms involved (bottom) as well as the possible outcomes after DNA repair, which include normal cell growth if the repair was successful, and growth arrest or programmed cell death if the damage was unable to be repaired. ss: single-stranded, dd: double-stranded.
DNA damage will activate a series of sensors, transducers and effectors in coordinating and regulating the DDR mechanism [27][28]. DNA damage that occurs at the chromosome is primarily coordinated by the phosphatidylinositol-3-kinase-related protein kinase (PIKK) family [29][30]. The primary signaling kinases of the PIKK family that are involved in the DDR are the DNA-dependent protein kinase catalytic subunit (DNA PKcs), ATM and ATM and Rad3-related kinase (ATR) [31], mammalian target of rapamycin (mTOR) [32][33] and suppressor with morphological effect on genitalia family member (SMG1) [34].
The relationship between DNA damage and TRF2 is complicated as DNA damage could either upregulate or downregulate TRF2 expression [35][36], whereas the disruption in the telomere integrity and function, such as mutation of TRF2, has been shown to increase DDR [37]. The occurrence of DNA damage has been reported to transiently increase TRF2 expression [35], while accumulation of non-telomeric DNA damage would further cause degradation of TRF and telomere shortening, which will further lead to DNA instability [36]. The changes of TRF2 expression with DNA damage are also reflected in cancers. Elevated TRF2 expression has been identified as frequently occurring during transformation of breast tumor cells as well as in colorectal cancers, which promote tumor formation and progression [38][39][40]. On the other hand, downregulation of TRF2 has been found in Hodgkin’s lymphoma [41][42]. This loss of TRF2 in Hodgkin’s lymphoma disrupts the telomere-TRF2 interaction, leading to chromosomal rearrangement [43]. The unique role of TRF2 is even more puzzling when an increased expression of TRF2 would also induce DNA damage, which is mostly found in some cancer cells [38][39][44][45][46][47]. The overexpression of TRF2 was found to cause replication stalling at the telomeres; hence, it causes telomere attrition [48].
Over the years, extensive research has been conducted to investigate the connection between telomere protection and the DDR, where a number of interconnections between the factors have been established. It has been reported that TRF2 expression can be regulated at both the transcriptional and post-transcriptional levels depending on the cell types and other factors [35], as it has been shown that TRF2 mRNA level is similar [40] but the protein level is different in different types of cells [49]. However, the regulation of TRF2 levels may also be regulated by post-translational modification, such as phosphorylation, which may affect the stability of TRF2 protein.

2. TRF2 Post-Translational Modification and Its Involvement with DDR

There are not many reports on the post-transcriptional modifications (PTM) of TRF2 that occur to modulate its function in the biological processes. To date, the modifications of TRF2 are known to assist in regulating its stability, binding activity and localization, either at the telomeres or outside of the telomeres [50]. Several PTM sites have been found at different domains of TRF2 as shown in the PhosphoSites database [51], where the phosphorylation event has taken up the most. More than 150 entries, including research findings and technical notes, have reported on Ser365 phosphorylation of TRF2, indicating that this phosphorylation may have an important role in regulating TRF2 functions. It has been demonstrated that phosphorylation of TRF2 at Ser365 by CDK [52] coordinates the assembly and disassembly of t-loops during the cell cycle, which protects telomeres from replication stress and an unscheduled DNA damage response [53]. In another study, phosphorylation of TRF2 on serine 323 by extracellular signal-regulated kinase (ERK1/2) was found in both normal and cancer cells [54]. Furthermore, human TRF2 has been reported to contain two highly conserved PIKK phosphorylation sites at Thr188 and Ser368, which can phosphorylate ATM upon induction of DNA damage [55][56]. The phosphorylation at Thr188 occurred 30 min post irradiation along with ATM-dependent factors, namely pp53 (ser15) and γH2AX, then gradually decreased and completely disappeared by 2 h [56]. Other downstream factors that will be activated by ATM kinase in response to radiation-induced DNA damage include Chk2 that will induce further DDR cascade [57]. Chk2 has been reported to phosphorylate TRF2 at Ser20, which will decrease its binding affinity at the telomeres [58][59]. This phosphorylation of TRF2 was thought to be important in the relocalization of TRF2 to non-telomeric DSBs. These findings suggest that phosphorylation of TRF2 may have a function in DNA repair.
SUMOylation is the attachment of a small conjugating enzyme (ubiquitin-like modifier, SUMO) to lysine residue of target proteins [60][61]. SUMOylation of TRF2 helps to stabilize it and assists in its binding to the telomeres [62] as well as protecting the telomeres from NHEJ [63]. MMS21 SUMO ligase of the SMC5/6 complex SUMOylates TRF2, which is essential for the recruitment of TRF2 to the telomeres, along with other shelterin subunits such as TRF1 and Rap1 [64][65]. However, SUMOylation of TRF2 was found to occur at dysfunctional telomeres where it causes alternative lengthening of the telomeres (ALT) [66]. Such modification may also cause the uncontrollable lengthening of the telomere length that is observed in some cancer cells [64]. TRF2 has also been shown to be SUMOylated by PIAS1 that preferred the telomere-unbound form, where the telomere-dissociated TRF2 will be ubiquitinated by RNF4 and degraded by a proteasome [62]. However, little is known of SUMOylation function in the mammalian cells, whereas the SUMOylation mechanism of TRF2 is still unknown.
RNF4 is a mammalian SUMO-targeted ubiquitin ligase that contains SIM and RING domains, which interacts with several SUMO-conjugated proteins to promote ubiquitination [67]. Ubiquitination targets protein for proteasome degradation. RNF4 acts together with PIAS1 in regulating the levels of TRF2 at the telomere, which is important in maintaining the proper function of TRF2 as the telomere protection [62][68]. RNF4 will disrupt the stability of SUMOylated TRF2 but not the unmodified TRF2 [62]. RNF4 has also been shown to be important in the DDR either at the telomeres or outside of the telomeres where it was found to be colocalized with other DDR factors and was found to have a function in the downstream of the ATM-kinase pathway [69]. Another essential ubiquitination of TRF2 is by Siah1, where the latter is activated by ATM in response to DNA damage [66]. The relationship between Siah1 and TRF2 also works as a positive feedback loop with p53 in regulating DDR and initiating DNA repair, where p53 was shown to induce Siah1, which represses TRF2, where low levels of TRF2 will increase activation of p53 via ATM kinase pathway [70]. Another recent finding of TRF2 PTM was its acetylation by P300 at lysine residue 293, which was thought to be important in TRF2 stabilization and binding efficiency at the telomeres [71]. P300 has been found to be essential in the activation and regulation of DDR as it acetylates various factors involved in DNA damage repair [72]. P300 was also found to acetylate another PTM enzyme, Poly(ADP-ribosyl)ation or PARsylation 1 (PARP1), which is one of the earliest responses of DDR in identifying the types of damage [73][74]. PARP1 will recruit other DDR factors at the site of DNA damage that will initiate the repair cascade [75][76]. PARP1 was further identified with Poly(ADP-ribosyl)ate TRF2, which will affect the binding of TRF2 at the telomeres [77]. However, this effect has not been shown at other chromosomal regions.
It has been reported that TRF2 recruited other repair factors at the damage site and acted as the early response to DDR, similar to p53 binding protein 1 (53BP1) and ATM [78][79][80]. However, TRF2 does not have the ability to repair DNA damage on its own; rather, it does so through interactions with multiple repair factors. Nonetheless, it plays an essential role in regulating and maintaining gene stability. These PTMs of TRF2 are thought to be the key in exploring the mechanisms involving TRF2 and DDR at other non-telomeric sites. PTM of TRF2 has been shown to be important in its involvement with DDR; however, it was only found to be specific at the telomeres [65][81]. Table 1 summarizes the PTMs of TRF2 by various modification enzymes.
Table 1. Post-transcriptional modifications of TRF2.
Modification Amino Acids Modifying Enzymes Function Reference (s)
Phosphorylation Ser20 Chk2 Phosphorylation of TRF2 by Chk2 decreases TRF2 binding to telomeric DNA. S20 phosphorylation is required for TRF2 interaction with G-rich RNA and recruitment of ORC to OriP. [58][59]
Ser365 CDK Regulates the assembly and disassembly of t-loop during the cell-cycle or DNA replication, which protects the telomeres from replicative stress. [53]
Thr188 ATM Early recruitment at the DNA break site and may be involved in DNA damage response/repair. [56][82]
Thr358 Aurora C Possible function in cell replication and unwinding of the chromosome. [83]
SUMOylation IK140TE, LK245SE, and RK333DE MMS21 Stabilization of TRF2 and recruitment at the telomeres. [64][65]
- PIAS1 Interacts with RNF4 to regulate TRF2 level at the telomeres. [62]
Ubiquitylation K173 K180 K184 Siah1 Siah1 is a p53-inducible E3 ligase with a C3H4-type RING finger domain. Knockdown of Siah1 stabilizes TRF2 and telomere length maintenance. [70]
- RNF4 Interacts together with PIAS1 in modulating TRF2 role in telomere maintenance and protection through regulating the level of TRF2 at the telomeres. Acts downstream of the ATM-kinase pathway in DDR. [62][69]
Acetylation K293 P300 Required for TRF2 stabilization and efficient binding at the telomeres. [71]
Poly(ADP-ribosyl)ation or PARsylation - PARP1, PARP2 Reduces the binding of TRF2 to telomeres that may contribute to dysfunctional telomeres. [77][84]

3. TRF2 Protects Telomeres by Blocking the Activation of DDR

TRF2 is composed of four distinct domains: (1) the Myb domain (similar to TRF1), which confers specificity for TTAGGG repeats of the telomeres; (2) the N-terminal basic domain; (3) the TRF homology (TRFH) domain, which is involved in homodimerization with TRF1 and binding to accessory factors; and (4) the hinge domain, which mediates the interactions with Rap1 and TIN2. The main domains of TRF2 that bind to the DNA sequence are the N-terminal and C-terminal Myb domains [85]. TRF2, along with other shelterin complex subunits, primarily functions to protect the telomere end from being recognized as a DNA break [86][87] as well as from end-to-end fusions [88]. The binding of TRF2 via its binding domains at the telomeric sequence safeguards the t-loop structure of telomeres from homologous recombination and protects the telomere end from being recognized as a DNA break [89].
As mentioned above, TRF2 has been reported as actively inhibiting the DDR pathway, namely the ATM kinase, from recognizing the telomere as a DNA break, thus protecting the genomic integrity [90]. During DNA replication, the ‘closed’ state of the telomeres will be unfolded to become the ‘open’ state, in which the t-loop unfolds and exposes the 3′-overhang. These uncapped telomeres could be recognized as a DSB and detected by the DDR pathway factors, thus leading to unwanted end-to-end fusion of the telomere end [56][91]. TRF2 inhibition of DDR has been shown to be important in maintaining telomere length and stability, which could lead to cancer or other age-related diseases [92].
The shelterin complex, specifically TRF2 and POT1, can inhibit the ATM and ATR kinases, respectively, from recognizing the telomeres as a break, where ATM recognition at the telomeres was shown in TRF2-deficient cells [93][94] and the repression of ATR was elevated after POT1 deletion [94]. TRF2 and POT1 inhibit the ATM and ATR independently. Furthermore, TRF2 protection at the telomeres is only through the inhibition of the ATM and not the ATR, which is evidenced by the fact that deletion of TRF2 did not induce any activation of Chk1, which is downstream of the ATR pathway [59][95] but affected the activation of the downstream factors of ATM pathway [96]. Moreover, ATR inhibition was shown to have no effect on the telomeres-dysfunction induced foci (TIF) formation [94], a phenomenon occurring when the chromosome ends become too short or become uncapped and are prone to be recognized as a DNA break by the DDR [37][97]. Nonetheless, TIF formation recruited 53BP1, which was found to be induced in the absence of TRF2 [37].
The mechanism of ATM inhibition by TRF2 at the telomeres needs to be further explored. The next section will further discuss TRF2 inhibition on ATM kinase and its downstream factors during DDR.

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Yogeswaran Lokanathan
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