CHROMATIN STRUCTURE AND DNA DAMAGE RESPONSE
1Avicenna tajik State Medical University, Dushanbe, tajikistan
Genomic integrity is constantly exposed to the products of metabolic activities and environmental processes that can induce DNA damage. A well-organized network of signaling cascade, designated as DNA damage response (DDR), encompasses systems of damage detection, cell-cycle check-point activation and repair mechanisms. The DNA damage pathways involve not only naked DNA strands but also higherorder chromatin components, such as histone variants and heterochromatin proteins. Any impediment of this regulation process may cause extensive damage and trigger the growth of tumours. The alterations in chromatin architecture occur during transcription and replication and are required to provide the accessibility of proteins to DNA strands. There is increasing evidence that DNA repair is also accompanied by the chromatin remodeling, particularly in the case of efficient detection and repair of DSBs where chromatin structure and nucleosome organization represent a significant barrier.
Keywords: DNA damage, ATM, ATR, chromatin, DSBs, DDR.
- Wang G, Vasquez KM. Effects of replication and transcription on DNA structure-related genetic instability. Genes (Basel). 2017;8(1):453-9.
- Benada J, Macurek L. Targeting the checkpoint to kill cancer cells. Biomolecules. 2015;5(3):1912-37.
- Cann KL, Dellaire G. Heterochromatin and the DNA damage response: the need to relax. Biochemistry and Cell Biology-Biochimie Et Biologie Cellulaire. 2011;89:45-60.
- Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Löbrich M, Jeggo PA. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Molecular cell. 2008;31:167-177.
- Lee JH, Paull TT. Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene. 2007;26:7741-8.
- Finlay MR, Griffin RJ. Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family. Bioorg Med Chem Lett. 2012; 22(17):5352-9.
- Regal JA, Festerling TA, Buis JM, Ferguson DO. Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms. Hum Mol Genet. 2013;22(25):5146-59.
- Anika MW, Anderson JR. ATM and ATR as therapeutic targets in cancer. Pharmacology & Therapeutics. 2015;149:124-138.
- Shiloh Y, Ziv Y. The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Bio. 2013;14:197-210.
- Komatsu K. NBS1 and multiple regulations of DNA damage response. J Radiat Res. 2016;57(Suppl 1):i11-i17.
- Sak A, Stuschke M. Use of γH2AX and other biomarkers of double-strand breaks during radiotherapy. Seminars in Radiation Oncology. 2010; 20(4):223-31.
- Gatei M, Jakob B, Chen P. ATM protein-dependent phosphorylation of Rad50 protein regulates DNA repair and cell cycle control. J Biol Chem. 2011;286:31542-556.
- Marine J-C, Lozano G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 2010;17:93-102.
- Sullivan KD, Gallant-Behm CL, Henry RE, Fraikin JL, Espinosa JM. The p53 circuit board. Biochim Biophys Acta. 2012;1825:229-244.
- Smith J, Tho LM, Xu N, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73-112.
- Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes & Development. 2001;15:2177-96.
- Cimprich K, Cortez D. ATR: An essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008;9:616-27.
- Dai Y, Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res. 2011;16:376-83.
- Errico A, Costanzo V. Mechanisms of replication fork protection: A safeguard for genome stability. Crit Rev Biochem Mol Biol. 2012;47:222-35.
- Goto H, Izawa I, Li P, Inagaki M. Novel regulation of checkpoint kinase 1: Is checkpoint kinase 1 a good candidate for anti-cancer therapy? Cancer Sci. 2012;103(7):1195-200.
- Demidova AR, Aau MY, Zhuang L, Yu Q. Dual regulation of Cdc25A by Chk1 and p53-ATF3 in DNA replication checkpoint control. J Biol Chem. 2009;284(7):4132-9.
- Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell. 2007;11(2):175-89.
- Melixetian M, Klein DK, Sørensen CS, Helin K. NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint. Nat Cell Biol. 2009;11(10):1247-53.
- Matsuoka S, Ballif BA, Smogorzewska A. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316 :1160-6.
- Cazzalini O, Scovassi AI, Savio M, Stivala LA, Prosperi E. Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutat Res. 2010;704(1-3):12-20.
- Iyama T, Wilson DM. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair (Amst). 2013;12(8):620-36.
- Landau DA, Wu CJ. Chronic lymphocytic leukemia: Molecular heterogeneity revealed by high-throughput genomics. Genome Med. 2013;5(5):47.
- Lavin MF. Ataxia-telangiectasia: From a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008;9:759-69.
- Ruzankina Y, Pinzon-Guzman C, Asare A. Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell. 2007;1:113-26.
- Groth A, Rocha W, Verreault A, Almouzni G. Chromatin challenges during DNA replication and repair. Cell. 2007;128(4):721-33.
- Murray JM, Stiff T, Jeggo PA. DNA double-strand break repair within heterochromatic regions. Biochemical Society Transactions. 2012;40:173-8.
- Campos EI, Reinberg D. Histones: annotating chromatin. Annu Rev Genet, 2009;43:559-99.
Normatova Makhliyo Abdurakhmonovna, MD, PhD Senior Researcher of the Department of Stem Cells at Avicenna Tajik State Medical University
Address for correspondence:
Normatova Makhliyo Abdurakhmonovna
Senior Researcher of the Department of Stem Cells Avicenna Tajik State Medical University
734003, Republic of Tajikistan, Dushanbe, Rudaki Avenue, 139,
Tel.: (+992) 985 283444