MMSL 2011, 80(4):169-177 | DOI: 10.31482/mmsl.2011.023
ROLE OF γ-H2AX IN DNA-DAMAGE RESPONSE AND ITS POSSIBLE CLINICAL APPLICATIONSReview article
- 1 Department of Radiobiology, Faculty of Military Health Sciences, University of Defence, Hradec Králové, Czech Republic
- 2 Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University in Prague, Czech Republic
The integrity of the human genome is constantly threatened by exogenous or endogenous genotoxic agents that cause DNA damage. The ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) are considered as the most deleterious forms of DNA damage which could lead to genomic instability and to cancer development, if left unrepaired. The DNA damage response (DDR) is comprised of a network of proteins that cooperate to regulate cell cycle progression and repair of DNA lesions. Our understanding of molecular basis of repair processes and of functions of repair proteins, as well as understanding of chromatin modifications may provide new possibilities in improvement of cancer management. Phosphorylation of histone variant H2AX at serine 139 (γ-H2AX) and formation of γ-H2AX repair foci seems to be the most sensitive DNA damage marker in the chromatin flanking the free DNA double-stranded ends in DSBs. Monitoring of γ-H2AX levels can serve for early indication of cancer development, as biomarker of cancer therapy efficiency or as a biodosimetric marker of radiation exposure.
Keywords: DNA damage response; ionizing radiation; double-strand breaks; γ-H2AX, cancer biomarker; biodosimetry
Received: October 17, 2011; Revised: November 29, 2011; Published: December 9, 2011 Show citation
References
- Shurylak I.; Sachs R.K.; Hlatky L.; Little M.P.; Hahnfeldt P.; Brenner D.J. Radiation-induced leukemia at doses relevant to radiation therapy: modelling mechanism and estimating risks. J. Natl. Cancer Inst. 2006, 98, 1794-1806.
Go to original source...
Go to PubMed...
- Hall E.J.; Brenner D.J. Cancer risks from diagnostic radiology. Br. J. Radiol. 2008, 81, 362-378.
Go to original source...
Go to PubMed...
- Kiang J.G.; Garrison B.R.; Gorbunov N.V. Radiation combined injury: DNA damage, apoptosis and autophagy. Adapt. Med. 2010, 2, 1-10.
- Marchetti F.; Coleman M.A.; Jones I.M.; Wyrobek A.J. Candidate protein biodosimeters of human exposure to ionizing radiation. Int. J. Radiat. Biol. 2006,82, 605-639.
Go to original source...
Go to PubMed...
- Dickey J.S.; Redon Ch.E.; Nakamura A.J.; Baird B.J.; Sedelnikova O.A.; Bonner W.M. H2AX: functional roles and potential applications. Chromosoma 2009, 118, 683-692.
Go to original source...
Go to PubMed...
- Redon Ch.E.; Dickey J.S.; Bonner W.M.; Sedelnikova O.A. γ-H2AX as a biomarker of DNA damage induced by ionizing radiation in human peripheral blood lymphocytes and artificial skin. Adv. Space Res. 2009, 43, 1171-1178.
Go to original source...
Go to PubMed...
- Bennett C.B.; Lewis A.L.; Baldwin K.K.; Resnick M.A. Lethality induced by a 1017 single site-specific double-strand break in a dispensable yeast plasmid, 1018. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5613-5617.
Go to original source...
Go to PubMed...
- Ward J.F. DNA damage and repair. In: W.A.G. and M.N. Varna (Ed.). Physical and Chemical Mechanisms in Molecular Radiation Biology. Plenum Press, New York 1991, 403-421.
Go to original source...
- Collis J.S.; DeWeese T.L.; Jeggo A.P.; Parker A.R. The live and death of DNA-PK. Oncogene 2005, 24, 949-961.
Go to original source...
Go to PubMed...
- Wyman C.; Kanaar R. DNA double-strand break repair: all's well that ends well. Annu. Rev. Genet. 2006, 40, 363-383.
Go to original source...
Go to PubMed...
- Valerie K.; Povirk L.F. Regulation and mechanisms of mammalian double-strand break repair. Oncogene 2003, 22, 5792-5812.
Go to original source...
Go to PubMed...
- Takata M.; Sasaki M.S.; Sonoda E.; Morrison C. et al. Homologous recombination and non-homologous end joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 1998, 17, 5497-5508.
Go to original source...
Go to PubMed...
- Dobbs T.A; Tainer J.A.; Lees-Miller S. A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation. DNA Repair 2010, 9, 1307-1314.
Go to original source...
Go to PubMed...
- Meek K.; Douglas P.; Cui X.; Ding Q.; Lee-Miller S. Trans-autophosphorylation at DNA-dependent protein kinase's two major autophosphorylation site clusters facilitates end processing but not end joining. Mol. Cell. Biol. 2007, 27, 3881-3890.
Go to original source...
Go to PubMed...
- Petermann E.; Helleday T. Pathways of mammalian replication fork restart. Nat. Rev. Mol.Cell Biol. 2010, 11, 683-687.
Go to original source...
Go to PubMed...
- Beucher A.; Birraux L.; Tchouandong O,; Barton O.et al. ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. EMBO J. 2009, 28, 3413-3427.
Go to original source...
Go to PubMed...
- Shrivastav M.; DeHaro L.P.;nickoloff J.A.Regulation of DNA double-strand break repair pathway choice. Cell Res. 2008,18,137-147.
Go to original source...
Go to PubMed...
- McKinnon P.J. ATM and ataxia telangiectasia. EMBO Reports, 2004, 5,772-776.
Go to original source...
Go to PubMed...
- Lamarche B.J.; Orazio N.I.; Weitzman M.D. The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett. 2010, 584, 3682-3695.
Go to original source...
Go to PubMed...
- Milkos G.L.; John B. Heterochromatin and satellite DNA in man: properties and prospects. Am. J. Hum. Genet. 1979, 31, 264-280.
- Goodarzi A.A.; Jeggo P.; Lobrich M. The influence of heterochromatin on DNA double strand break repair: Getting strong, silent type to relax. DNA Repair 2010, 9, 1273-1282.
Go to original source...
Go to PubMed...
- Rogakou E.P.; Pilch D.R.; Orr A.H.; Ivanova V. S.; Bonner W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 1998, 273, 5858-5868.
Go to original source...
Go to PubMed...
- Sedelnikova O.A.; Pilch D.R.; Redon C.; Bonner W.M. Histone H2AX in DNA damage repair. Cancer Biol. Ther. 2003, 2, 233-235.
Go to PubMed...
- Stucki M.; Jackson S.P. γ-H2AX and MDC1: Anchoring the DNA-damage-response, machinery to broken chromosomes. DNA Repair 2006, 5, 534-543.
Go to original source...
Go to PubMed...
- Stiff T.; O'Driscoll M.; Rief N.; Iwabuchi K.; Lobrich M.; Jeggo P. ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res. 2004, 64, 2390-2396.
Go to original source...
Go to PubMed...
- Fernandez-Capetillo O.; Lee A.; Nussenzweig M.; Nussenzweig A. H2AX: the histone guardian of the genome. DNA Repair 2004, 3, 959-967.
Go to original source...
Go to PubMed...
- Cheung P.; Allis C.D.; Sassone-Corsi P. Signalling to chromatin through histone modifications. Cell 2000, 103, 263-271.
Go to original source...
Go to PubMed...
- Redon C.; Pilch D.; Rogakou E.; Sedelnikova O.A.; Newrock K.; Bonner W. Histone H2A variants H2AX and H2AZ. Curr. Opin. Genet. 2002, 12, 162-169.
Go to original source...
Go to PubMed...
- Kinner A.; Wu W.; Staudt Ch.; Iliakis G. γ-H2AX in recognition and signalling of DNA double-strand breaks in the context of chromatin. Nucl. Acid Res. 2008, 36, 5678-5694.
Go to original source...
Go to PubMed...
- Cook P.J.; Ju B.G.; Telese F.; Wang X.; Glass C.K.; Rosenfeld M.G. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 2009, 458, 591-596.
Go to original source...
Go to PubMed...
- Xiao A.; Li H.; Shechter D.; Ahn S.H.; Fabrizio L.A.; Erdjument-Bromage H.; Ishibe-Murakami S.; et al. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature 2009, 457, 57-62.
Go to original source...
Go to PubMed...
- Lukas J.; Bartek J. DNA repair: New tales of an old tail. Nature, 2009, 458, 581-583.
Go to original source...
Go to PubMed...
- Luijsterburg M.S.; van Attikum H. Chromatin and the DNA damage response: The cancer connection. Molecular Oncology 2011, 5, 349-367.
Go to original source...
Go to PubMed...
- Steward G.S.; Wang B.; Bignell C.R.; Taylor A.M.R.; Elledge S.J. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 2003, 421, 961-966.
Go to original source...
Go to PubMed...
- Stucky M.; Clapperton J.; Mohannad D.; Yaffe M.; Smerdon S.; Jackson S. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 2005, 123, 1213-1226.
Go to original source...
Go to PubMed...
- Mochan T.A.; Venere M.; DiTullio R.A.; Halazonetis T.D. 53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage. Cancer Res. 2003, 63, 8586-8591.
Go to PubMed...
- Bekker-Jensen S.; Mailand N. Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair, 2010, 1219-1228.
Go to original source...
Go to PubMed...
- Mainland N.; Bekker-Jensen S.; Faustrup H.; Melander F.; Bartek J.; Lukas C.;et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 2007, 131, 887-900.
Go to original source...
Go to PubMed...
- Doil C.; Mainland N.; Bekker-Jensen S.; Menard P.; Larsen D.H.; Pepperkok R.; et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 2009, 136, 435-446.
Go to original source...
Go to PubMed...
- Lou Z.; Minter-Dykhouse K.; Wu X.; Chen J. MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature 2003, 421, 957-961.
Go to original source...
Go to PubMed...
- Lou Z.; Minter-Dykhouse K.; Franco S.; Gostissa M.; Rivera M.; Celeste A.; et al. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol. Cell 2006, 21, 187-200.
Go to original source...
Go to PubMed...
- Unal E.; Arbel-Eden A,; Satter U.; Shroff R.; Lichten M.; Haber J.E.; Kohsland D. DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol. Cell 2004, 16, 991-1002.
Go to original source...
Go to PubMed...
- Downey M.; Durocher D. GammaH2AX as a checkpoint maintenance signal. Cell Cycle 2006, 5, 1376-1381.
Go to original source...
Go to PubMed...
- Fernandez-Capetillo O.;Chec H.T.; Celeste A. et al. DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat. Cell. Biol. 2002, 4, 993-997.
Go to original source...
Go to PubMed...
- Mukherjee B.; Kessinger C.; Kobayashi J.; Chen B.P.; Chen D.J.; Chatterjee A.; Burma S. DNA-PK phosphorylates histone H2AX during apoptotic DNA fragmentation in mammalian cells. DNA Repair 2006, 5, 575-590.
Go to original source...
Go to PubMed...
- Rothkamm K.; Lobrich M. Evidence of lack of DNA double-strand break repair in human cells exposed to very low X-ray doses. Proc. Natl. Acad. Sci. USA 2003, 100, 5057-5062.
Go to original source...
Go to PubMed...
- Sedelnikova O.A.; Rogakou E.P.; Panyutin I.G.; Bonner W.M. Quantitative detection of (125)IdU-induced DNA double-strand breaks with gamma-H2AX antibody. Radiat. Res. 2002, 158, 486-492.
Go to original source...
- Horn S.; Rothkamm K. Candidate protein biomarkers as rapid indicators of radiation exposure. Radiation Measurements 2011.
Go to original source...
- Sedelnikova O.A.; Bonner W.M. γ-H2AX in cancer cells: a potential biomarker for cancer diagnostics, prediction and recurrence. Cell Cycle 2006, 5, 2909-2913.
Go to PubMed...
- Halicka H.D.; Ozkaynak M.F.; Levendoglu-Tual O.; et al. DNA damage response as a biomarker in treatment of leukemia. Cell Cycle 2009, 8, 1720-1724.
Go to original source...
Go to PubMed...
- Havelek R.; Řezáčová M.; Šinkorová Z.; Zárybnická L.; Tichý A.; Vávrová J. Phosphorylation of histone H2AX as an indicator of received dose of gamma radiation after whole-body irradiation of rats. Acta Vet. Brno 2011, 80, 113-118.
Go to original source...
- Havelek R.; Řezáčová M.; Šinkorová Z.; Zárybnická L.; Pejchal J..; Vávrová J. Phosphorylation of histone H2AX in peripheral blood mononuclear cells after thoracic irradiation of rats. J. Appl. Biomed. 2011, 9, 209-218.
Go to original source...
- Redon C.E.; Nakamura A.J.; Gouliaeva K.; Rahman A.; Blakely W.F.; Bonner W.M. The Use of Gamma-H2AX as a biodosimeter for Total-Body Radiation Exposure in non-Human Primates. Plos One, 2010, 5, e15544.
Go to original source...
Go to PubMed...
- Goodarzi A.A.; Jeggo P.A. Irradiation induced foci (IRIF) as a biomarker for radiosensitivity. Mutat. Res.: Fundam. Mol. Mech. Mutagen. 2011, doi:10.1016/j.mrfmmm.2011.05.017.
Go to original source...
Go to PubMed...
- Chatterjee S.K.; Zetter B.R. Cancer biomarkers: Knowing the present and predicting the future. Future Oncology 2005, 1, 37-50.
Go to original source...
Go to PubMed...
- Bartkova J.; Horejsi Z.; Koed K.; et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 2005, 434, 864-870.
Go to original source...
Go to PubMed...
- Warters R.L.; Adamson P.J.; Pond C.D.; Leachman S.A. Melanoma cells express elevated levels of phosphorylated histone H2AX foci. J. Invest. Dermatol. 2005, 124, 807-817.
Go to original source...
Go to PubMed...
- Yu T.; MacPhail S.H.; Banath J.P.; Klokov D.; Olive P.L. Endogenous expression of phosphorylated histone H2AX in tumors in relation to DNA double-strand breaks and genomic instability. DNA Repair 2006, 5, 935-946.
Go to original source...
Go to PubMed...
- Risques R.A.; Lai L.A.; Brentnall T.A.; et al. Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. Gastroenterology 2008, 135, 410-418.
Go to original source...
Go to PubMed...
- Kao J.; Milano M.T.; Javaheri A.; Garofalo M.C,; Chmura S.J.; Weichselbaum R.R.; Kron S.J. Gamma-H2AX as a therapeutic target for improving the efficacy of radiation therapy. Curr. Cancer Drug Targets 2006, 6, 197-205.
Go to original source...
Go to PubMed...
- O'Connor M.J., Martin N.M.B.; Smith G.C.M. Targeted cancer therapies based on the inhibition of DNA strand break repair. Oncogene 2007, 26, 7816-7824.
Go to original source...
Go to PubMed...
- Martin N.M.B. DNA repair inhibition and cancer therapy. J. Photochem. Photobiol. 2001, 63, 162-170.
Go to original source...
Go to PubMed...
- Tichy A.; Muthna D.; Vavrova J.; Pejchal J.; et al. Caffeine-suppressed ATM pathway leads to decreased p53 phosphorylation and increased programmed cell death in gamma-irradiated leukemic MOLT-4 cells. J. Appl. Biomed. 2011, 9, 49-56.
Go to original source...
- Hickson I.; Zhao Y.; Richardson C.J.; Green S.J.; Martin N.M.; et al. Identification and characterization of a novel and specific inhibitor of the Ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004, 64, 9152-9159.
Go to original source...
Go to PubMed...
- Zhao Y.; Huw D.T.; Batey M.A.; Cowell I.G.; Richardson C.J.; et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 2006, 66, 5354-5362.
Go to original source...
Go to PubMed...