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Long Non-coding RNAs
Long noncoding RNAs (lncRNAs) constitute important group of RNA molecules with various biological activities. Despite significant progress in the understanding of lncRNAs, pivotal functions of this class of molecules are emerging. Among these, role in DNA damage response (DDR) seems to be fundamental. Various lncRNAs were found to modulate DNA repair on different levels: through TP53 activity modulation at transcriptional and translational level, through recruitment of chromatin remodelers that modulate the access of DNA repair proteins to the site of damage, and by working as scaffolds and mediators for DNA repair proteins, and acting as sponges for various DNA-damage-associated miRNAs. Considering that, lncRNAs involvement in DDR constitute interesting field of research with numerous future applications, such as development of new targeted anticancer therapies.
Long noncoding RNAs (lncRNAs) comprise an abundant group of diverse RNA molecules with length exceeding 200 nucleotides . These non-coding RNAs perform different biological functions, including transcription regulation, modulation of chromatin structure through DNA methylation, histone modification and chromatin remodeling, posttranscriptional regulation, modulation of protein activity, and others extensively reviewed elsewhere . The function of lncRNAs is highly dependent on their subcellular localization. There are three different fractions of lncRNAs reckoning their place of action: cis nuclear lncRNAs that are localised close to their sites of transcription, lncRNAs that perform functions in the nucleus but regulate expression of genes distant from their own sites of transcription (in a trans-dependent manner) and lncRNAs that need to be exported (transported) to cytoplasm to perform their regulatory functions . Furthermore, based on their immediacy to protein coding genes, lncRNAs have been classified into several groups: sense, antisense, intronic, intergenic transcripts and pseudogenes.
Significant scientific progress has been made regarding the role of lncRNAs in DNA repair. LncRNAs are considered to play a prominent role in DSB repair. They have been shown to alter DSB repair through several mechanisms: (a) through TP53 activity modulation at transcriptional and translational level, (b) through recruitment of chromatin remodelers that modulate the access of DNA repair proteins to the site of damage, (c) by working as scaffolds and mediators for DNA repair proteins, and (d), last but not least, acting as sponges for various DNA-damage-associated miRNAs .
2. Long Non-coding RNAs in DNA Damage Response
Double strand breaks (DSBs) occurrence lead to recruitment of DNA damage sensors, such as MRN complexes and Ku proteins, at the site of DNA damage. This is followed by firing of signaling cascades and downstream protein activation . The key component activated upon DSB is ATM protein kinase. ATM phosphorylates H2AX histones at the site of damage, leading to γH2AX foci formation at break sites . Moreover, ATM activation leads to CHK1- and CHK2-dependent TP53 phosphorylation . TP53, often perceived as a “guardian of the genome”, is one of the best-studied tumor suppressor proteins. It has been estimated that almost half of human tumors carry a mutation in the TP53 gene. Activation of TP53 upon DNA damage leads to either cell cycle arrest or apoptosis depending on the nature and severity of the damage. TP53 acts as a key transcriptional regulator of different proteins inside the cell . Moreover, CHK1/2 activation leads to inhibition of cyclin-dependent kinase activity that slows down or arrests the cell cycle in G1-S or G2-M phase . The expression of lncRNAs can be induced following DNA damage. This may occur in a TP53-dependent manner. Additionally, some lncRNAs may regulate expression of TP53 downstream targets, further complicating the interactions.
The examples of TP53-linked lncRNAs are lincRNA-p21  and PANDA , both located upstream of CDKN1A (p21) gene. P21 is a protein that binds to certain CDKs, forming inactive complexes that compromise cell cycle arrest and apoptosis. lincRNA-p21 was shown to repress transcription induced by TP53 through interaction with heterogeneous nuclear ribonucleoprotein-K (hnRNP-K), which constitutes an important component of repressor complexes. These complexes are recruited to the promoters of downstream TP53 transcriptional targets and prevent effective TP53-mediated transcription . In contrast, CDKN1A upstream lncRNA, DINO, was shown to stabilize TP53 protein and stimulate its transactivatory activity . Other lncRNAs, like WRAP3α lncRNA directly bind to TP53 mRNA after DNA damage to stabilize the protein, and thus affect its level inside the cell . LINP1, on the other hand, works as a scaffold for NHEJ proteins (Ku70–Ku80 and DNA-PKcs) during DNA repair, where it promotes the religation of broken DNA strand ends . Another lncRNA worth mentioning, MALAT1, constitutes a link between sirtuins and TP53. MALAT1 sequesters DBC1, a negative regulator of SIRT1, and thus promotes SITR1-mediated deacetylation of TP53. This results in altered expression of TP53 target genes and TP53-linked lncRNAs . Misteli et al. demonstrated that intergenic lncRNA DDSR1 expression could be elevated in response to DNA-damaging drugs. DDSR1 induction is greatly dependent on ATM and NF-Κb activation but TP53 is not necessary for its induction—nevertheless, it still may regulate its expression. Interestingly, DDSR1 can regulate TP53-target gene expression. Moreover, DDSR1 knockdown leads to impaired homologous recombination (HR) and upregulation of TP53-dependent gene expression, especially of those genes that contribute to cell proliferation . The choice between HR and NHEJ repair pathways is further attributed to two noncoding RNAs—CUPID1 and CUPID2—located in the enhancer region of the CCND1 gene, coding for cyclin D1 . The lncRNA GUARDIN plays an important role in genome stability maintenance. Sequestering of miRNA-23a by GUARDIN leads to sustained expression of telomeric repeat factor 2 (TRF-2), which prevents chromosome end fusion. Furthermore, GUARDIN regulates the stability of BRCA1 and promotes its association with BRCA1-associated RING domain protein (BARD1) for effective HR . TODRA, an antisense lncRNA transcribed upstream of the RAD51 recombinase gene, has also been shown to be implicated in HR, where it regulates RAD51 expression and protein activity . Numerous lncRNAs have been confirmed to play a role in DDR. These include the following lncRNAs: ANRIL , BARD1 9´L , Gadd7 , HOTAIR , JADE , LincROR , LIRRE , MDC1-AS , NEAT1 , PCAT-1 , PINCR , PINT , PURPL , PR-lncRNA-1, PR-lncRNA-10 , TERRA .
The importance of lncRNAs in cellular physiology is certainly unquestionable. LncRNAs play a significant role in DNA repair through various cis and trans mechanisms. Besides the influence of lncRNAs in gene expression, they can act as scaffolds for DNA repair proteins or work as miRNA scavengers, affecting both the activity and abundance of DDR components. It remains unclear how the primary and secondary structure of lncRNAs molecules affects DDR protein activity. The growth and progress of advanced RNA-directed technologies allow researchers to explore functions of genome “dark matter”. The greatest burden, however, is the tremendous and ambiguous amount of data generated during RNA-seq, which requires further interpretation. Moreover, lncRNA action is highly context-dependent, and the subcellular localization of RNA molecules seems to be fundamental. The dynamics of how the compartmentalization is achieved constitute another question. Plenty of studies have been carried out to clarify the role of lncRNAs in cancer. These require a more comprehensive approach encompassing the complex signaling networks related to lncRNAs. Determination of possible tumor-inducing and tissue-specific lncRNAs raise hopes for development of new targeted antineoplastic agents .
The entry is from 10.3390/ijms21113934
- Ling-Ling Chen; Linking Long Noncoding RNA Localization and Function. Trends in Biochemical Sciences 2016, 41, 761-772, 10.1016/j.tibs.2016.07.003.
- Guohui Wan; Rohit Mathur; Xiaoxiao Hu; Yunhua Liu; Xinna Zhang; Guang Peng; Xiongbin Lu; Long non-coding RNA ANRIL (CDKN2B-AS) is induced by the ATM-E2F1 signaling pathway.. Cellular Signalling 2013, 25, 1086-95, 10.1016/j.cellsig.2013.02.006.
- Vijay Suresh Akhade; Debosree Pal; Chandrasekhar Kanduri; Long Noncoding RNA: Genome Organization and Mechanism of Action. Advances in Experimental Medicine and Biology 2017, 1008, 47-74, 10.1007/978-981-10-5203-3_2.
- Roopa Thapar; Regulation of DNA Double-Strand Break Repair by Non-Coding RNAs. Molecules 2018, 23, 2789, 10.3390/molecules23112789.
- Makoto Hayashi; Jan Karlseder; DNA damage associated with mitosis and cytokinesis failure.. Oncogene 2013, 32, 4593-601, 10.1038/onc.2012.615.
- Monika Podhorecka; Andrzej Skladanowski; Przemyslaw Bozko; H2AX Phosphorylation: Its Role in DNA Damage Response and Cancer Therapy. Journal of Nucleic Acids 2010, 2010, 1-9, 10.4061/2010/920161.
- Stephen P Jackson; Jiri Bartek; The DNA-damage response in human biology and disease. Nature 2009, 461, 1071-8, 10.1038/nature08467.
- David R Raleigh; Daphne Haas-Kogan; Molecular targets and mechanisms of radiosensitization using DNA damage response pathways. Future Oncology 2013, 9, 219-233, 10.2217/fon.12.185.
- Rosa Pennisi; Paolo Ascenzi; Alessandra Di Masi; Hsp90: A New Player in DNA Repair?. Biomolecules 2015, 5, 2589-2618, 10.3390/biom5042589.
- Maite Huarte; Mitchell Guttman; David M. Feldser; Manuel Garber; Magdalena J. Koziol; Daniela Kenzelmann-Broz; Ahmad M. Khalil; Or Zuk; Ido Amit; Michal Rabani; et al. A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response. Cell 2010, 142, 409-19, 10.1016/j.cell.2010.06.040.
- Tiffany Hung; Yulei Wang; Michael F. Lin; Ashley K. Koegel; Yojiro Kotake; Gavin D. Grant; Hugo M. Horlings; Nilay Shah; Christopher Umbricht; Pei Wang; et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nature Genetics 2011, 43, 621-9, 10.1038/ng.848.
- Adam Schmitt; Julia T. Garcia; Tiffany Hung; Ryan A. Flynn; Ying Shen; Kun Qu; Alexander Y. Payumo; Ashwin Peres-Da-Silva; Daniela Kenzelmann Broz; Rachel Baum; et al. An inducible long noncoding RNA amplifies DNA damage signaling. Nature Genetics 2016, 48, 1370-1376, 10.1038/ng.3673.
- Salah Mahmoudi; Sofia Henriksson; Martin Corcoran; Cristina Méndez-Vidal; Klas G. Wiman; Marianne Farnebo; Wrap53, a Natural p53 Antisense Transcript Required for p53 Induction upon DNA Damage. Molecular Cell 2016, 64, 1009, 10.1016/j.molcel.2016.11.027.
- Youyou Zhang; Qun He; Zhongyi Hu; Yi Feng; Lingling Fan; Zhaoqing Tang; Jiao Yuan; Weiwei Shan; Chunsheng Li; Xiaowen Hu; et al. Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer. Nature Structural & Molecular Biology 2016, 23, 522-530, 10.1038/nsmb.3211.
- Ja-Eun Kim; Junjie Chen; Zhenkun Lou; DBC1 is a negative regulator of SIRT1. Nature 2008, 451, 583-586, 10.1038/nature06500.
- Jingjie Yi; Jianyuan Luo; SIRT1 and p53, effect on cancer, senescence and beyond.. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2010, 1804, 1684-9, 10.1016/j.bbapap.2010.05.002.
- Yi-Hui Lin; Jian Yuan; Huadong Pei; Tongzheng Liu; David K. Ann; Zhenkun Lou; KAP1 Deacetylation by SIRT1 Promotes Non-Homologous End-Joining Repair. PLOS ONE 2015, 10, e0123935, 10.1371/journal.pone.0123935.
- Vivek Sharma; Simran Khurana; Nard Kubben; Kotb Abdelmohsen; Philipp Oberdoerffer; Myriam Gorospe; Tom Misteli; A BRCA 1‐interacting lnc RNA regulates homologous recombination. EMBO reports 2015, 16, 1520-1534, 10.15252/embr.201540437.
- Sophie Polo; Andrew N. Blackford; J. Ross Chapman; Linda Baskcomb; Serge Gravel; Andre Rusch; Anoushka Thomas; Rachel Blundred; Philippa Smith; Julia Kzhyshkowska; et al. Regulation of DNA-End Resection by hnRNPU-like Proteins Promotes DNA Double-Strand Break Signaling and Repair. Molecular Cell 2012, 45, 505-16, 10.1016/j.molcel.2011.12.035.
- Joshua A. Betts; Mahdi Moradi Marjaneh; Fares Al-Ejeh; Yi Chieh Lim; Wei Shi; Haran Sivakumaran; Romain Tropee; Ann-Marie Patch; Michael B. Clark; Nenad Bartonicek; et al. Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage. The American Journal of Human Genetics 2017, 101, 255-266, 10.1016/j.ajhg.2017.07.007.
- Wang Lai Hu; Lei Jin; An Xu; Yu Fang Wang; Rick F. Thorne; Xu Dong Zhang; Mian Wu; GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability. Nature 2018, 20, 492-502, 10.1038/s41556-018-0066-7.
- Inbal Gazy; David A. Zeevi; Paul Renbaum; Sharon Zeligson; Lital Eini; Dana Bashari; Yoav Smith; Amnon Lahad; Michal Goldberg; Ron Ginsberg; et al. TODRA, a lncRNA at the RAD51 Locus, Is Oppositely Regulated to RAD51, and Enhances RAD51-Dependent DSB (Double Strand Break) Repair. PLOS ONE 2015, 10, e0134120, 10.1371/journal.pone.0134120.
- Maxim Pilyugin; Irmgard Irminger-Finger; Long non-coding RNA and microRNAs might act in regulating the expression of BARD1 mRNAs. The International Journal of Biochemistry & Cell Biology 2014, 54, 356-367, 10.1016/j.biocel.2014.06.018.
- M. Christine Hollander; Isaac Alamo; A J Fornace; A Novel DNA Damage-Inducible Transcript, gadd7, Inhibits Cell Growth, but Lacks a Protein Product. Nucleic Acids Research 1996, 24, 1589-1593, 10.1093/nar/24.9.1589.
- Xuefeng Liu; Dan Li; Weimin Zhang; Mingzhou Guo; Qimin Zhan; Long non-coding RNA gadd7 interacts with TDP-43 and regulates Cdk6 mRNA decay. The EMBO Journal 2012, 31, 4415-4427, 10.1038/emboj.2012.292.
- Miao-Chih Tsai; Robert C. Spitale; Howard Y Chang; Long intergenic noncoding RNAs: new links in cancer progression.. Cancer Research 2011, 71, 3-7, 10.1158/0008-5472.CAN-10-2483.
- Ali R. Özeş; David F. Miller; Osman N. Özeş; Fang Fang; Yunlong Liu; Daniela Matei; Tim Huang; Kenneth P. Nephew; NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer.. Oncogene 2016, 35, 5350-5361, 10.1038/onc.2016.75.
- Guohui Wan; Xiaoxiao Hu; Yunhua Liu; Cecil Han; Anil K Sood; George A. Calin; Xinna Zhang; Xiongbin Lu; A novel non-coding RNA lncRNA-JADE connects DNA damage signalling to histone H4 acetylation. The EMBO Journal 2013, 32, 2833-2847, 10.1038/emboj.2013.221.
- Majdaddin Rezaei; Modjtaba Emadi-Baygi; Michèle J. Hoffmann; Wolfgang A. Schulz; Parvaneh Nikpour; Altered expression of LINC-ROR in cancer cell lines and tissues. Tumor Biology 2015, 37, 1763-1769, 10.1007/s13277-015-3933-x.
- Yang Jiao; Chang Liu; Feng-Mei Cui; Jia-Ying Xu; Jian Tong; Xiao-Fei Qi; Li-Li Wang; Wei Zhu; Long intergenic non-coding RNA induced by X-ray irradiation regulates DNA damage response signaling in the human bronchial epithelial BEAS-2B cell line. Oncology Letters 2014, 9, 169-176, 10.3892/ol.2014.2622.
- Yao Xue; Gaoxiang Ma; Zhensheng Zhang; Qiuhan Hua; Haiyan Chu; Na Tong; Lin Yuan; Chao Qin; Changjun Yin; Zhengdong Zhang; et al. A novel antisense long noncoding RNA regulates the expression of MDC1 in bladder cancer. Oncotarget 2014, 6, 484-493, 10.18632/oncotarget.2861.
- Carmen Adriaens; Laura Standaert; Jasmine Barra; Mathilde Latil; Annelien Verfaillie; Peter Kalev; Bram Boeckx; Paul W G Wijnhoven; Enrico Radaelli; William Vermi; et al. p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nature Medicine 2016, 22, 861-868, 10.1038/nm.4135.
- John R. Prensner; Matthew K. Iyer; O. Alejandro Balbin; Saravana Mohan Dhanasekaran; Qi Cao; J. Chad Brenner; Bharathi Laxman; Irfan A. Asangani; Catherine S Grasso; Hal D. Kominsky; et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nature Biotechnology 2011, 29, 742-749, 10.1038/nbt.1914.
- John R. Prensner; Wei Chen; Matthew K. Iyer; Q. Cao; Teng Ma; Sumin Han; Anirban Sahu; Rohit Malik; Kari Wilder-Romans; Nora Navone; et al. PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer.. Cancer Research 2014, 74, 1651-60, 10.1158/0008-5472.CAN-13-3159.
- John R. Prensner; Wei Chen; Sumin Han; Matthew K. Iyer; Qi Cao; Vishal Kothari; Joseph R. Evans; Karen E Knudsen; Michelle T. Paulsen; Mats Ljungman; et al. The long non-coding RNA PCAT-1 promotes prostate cancer cell proliferation through cMyc.. Neoplasia 2014, 16, 900-8, 10.1016/j.neo.2014.09.001.
- Ritu Chaudhary; Berkley Gryder; Wendy S Woods; Murugan Subramanian; Matthew F Jones; Xiao Ling Li; Lisa M Jenkins; Svetlana A Shabalina; Min Mo; Mary Dasso; et al. Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in human colorectal cancer cells by binding to Matrin 3. eLife 2017, 6, e23244, 10.7554/elife.23244.
- Oskar Marín-Béjar; Francesco Marchese; Alejandro Athie; Yolanda Sanchez; Jovanna González; Victor Segura; Lulu Huang; Isabel Moreno; Alfons Navarro; Mariano Monzó; et al. Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2. Genome Biology 2013, 14, R104-R104, 10.1186/gb-2013-14-9-r104.
- Oskar Marín-Béjar; Aina M. Mas; Jovanna González; Dannys Martinez; Alejandro Athie; Xabier Morales; Mikel Galduroz; Ivan Raimondi; Elena Grossi; Shuling Guo; et al. The human lncRNA LINC-PINT inhibits tumor cell invasion through a highly conserved sequence element. Genome Biology 2017, 18, 202, 10.1186/s13059-017-1331-y.
- Xiao Ling Li; Murugan Subramanian; Matthew F. Jones; Ritu Chaudhary; Deepak Singh; Xinying Zong; Berkley Gryder; Sivasish Sindri; Min Mo; Aaron Schetter; et al. Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer.. Cell Reports 2017, 20, 2408-2423, 10.1016/j.celrep.2017.08.041.
- Yolanda Sanchez; Victor Segura; Oskar Marín-Béjar; Alejandro Athie; Francesco Marchese; Jovanna González; Luis Bujanda; Shuling Guo; Ander Matheu; Maite Huarte; et al. Genome-wide analysis of the human p53 transcriptional network unveils a lncRNA tumour suppressor signature. Nature Communications 2014, 5, 5812, 10.1038/ncomms6812.
- Laura Maringele; David Lydall; EXO1-dependent single-stranded DNA at telomeres activates subsets of DNA damage and spindle checkpoint pathways in budding yeast yku70Δ mutants. Genes & Development 2002, 16, 1919-1933, 10.1101/gad.225102.
- Antonio Porro; Sascha Feuerhahn; Joachim Lingner; TERRA-Reinforced Association of LSD1 with MRE11 Promotes Processing of Uncapped Telomeres. Cell Reports 2014, 6, 765-776, 10.1016/j.celrep.2014.01.022.
- Wenyuan Zhao; Bin Shan; Dan He; Yuanda Cheng; Bin Li; Chunfang Zhang; Chaojun Duan; Recent Progress in Characterizing Long Noncoding RNAs in Cancer Drug Resistance.. Journal of Cancer 2019, 10, 6693-6702, 10.7150/jca.30877.