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The Epigenetic Biomarker γH2AX: From Bench to Clinical Trials

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Epigenetics, the Environment, and Children’s Health Across Lifespans

Abstract

Epigenetic factors exert their function by means of three mechanisms: (1) DNA methylation, (2) noncoding RNAs, and (3) histone posttranslational modifications. In this chapter, we focus on a histone posttranslational modification, the γ-phosphorylation of the histone H2AX. H2AX is a mammalian variant that belongs to the H2A histone family. In contrast with the other members of the family, H2AX has a unique phosphorylation site on its amino-terminal tail. Posttranslational modification involves a biological amplification mechanism where one double-strand break induces the γ-phosphorylation of thousands of H2AX molecules along megabase-long domains of chromatin, which are adjusted to the sites of double-strand breaks. Ongoing translational research on the γH2AX epigenetic biomarker is very dynamic and is expected to develop further, in order to serve monitoring for diverse pathologies and the evaluation of their therapies.

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References

  • Ashour, M. E., Atteya, R., & El-Khamisy, S. F. (2015). Topoisomerase-mediated chromosomal break repair: An emerging player in many games. Nature Reviews Cancer, 15, 137–151.

    Article  PubMed  CAS  Google Scholar 

  • Bekker-Jensen, S., Lukas, C., Melander, F., Bartek, J., & Lukas, J. (2005). Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. Journal of Cell Biology, 170(2), 201–11.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bridges, K. A., Hirai, H., Buser, C. A., Brooks, C., Liu, H., Buchholz, T. A., et al. (2011). MK-1775, a novel wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clinical Cancer Research, 17(2), 5638–48.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Celeste, A., Difilippantonio, S., Difilippantonio, M. J., Fernandez-Capetillo, O., Pilch, D. R., Sedelnikova, O. A., et al. (2003). H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell, 114, 371–83.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Celeste, A., Petersen, S., Romanienko, P. J., Fernandez-Capetillo, O., Chen, H. T., Sedelnikova, O. A., et al. (2002). Genomic instability in mice lacking histone H2AX. Science, 296(5569), 922–7.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Chen, H. T., Bhandoola, A., Difilippantonio, M. J., Zhu, J., Brown, M. J., Tai, X., et al. (2000). Response to RAG-mediated VDJ cleavage by NBS1 and gamma-H2AX. Science, 290(5498), 1962–5.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cheng, W.-H., Muftic, D., Muftuoglu, M., Dawut, L., Morris, C., Helleday, T., et al. (2008). WRN is required for ATM activation and the S-phase checkpoint in response to interstrand cross-link-induced DNA double-strand breaks. Molecular Biology of the Cell, 19(September), 3923–33.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Chronis, F., & Rogakou, E. P. (2007). Interplay between H2AX and 53BP1 pathways in DNA double-strand break repair response. In D. Gewirtz, S. E. Holt, & S. Grant (Eds.), Apoptosis, senescence, and cancer (pp. 243–263). Totowa, NJ: Humana. http://www.springer.com/gp/book/9781588295279.

  • Chuang, H. C., Kapuriya, N., Kulp, S. K., Chen, C. S., & Shapiro, C. L. (2012). Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells. Breast Cancer Research and Treatment, 134(2), 649–59.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cimprich, K. A., & Cortez, D. (2008). ATR: an essential regulator of genome integrity. Nature Reviews Molecular Cell Biology, 9(8), 616–27.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cooper, A., García, M., Petrovas, C., Yamamoto, T., Koup, R. A., & Nabel, G. J. (2013). HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature, 498, 376–9.

    Article  PubMed  CAS  Google Scholar 

  • Cruet-Hennequart, S., Villalan, S., Kaczmarczyk, A., O’Meara, E., Sokol, A. M., & Carty, M. P. (2014). Characterization of the effects of cisplatin and carboplatin on cell cycle progression and DNA damage response activation in DNA polymerase eta-deficient human cells. Cell Cycle, 8(18), 3043–54.

    Article  Google Scholar 

  • d’Adda di Fagagna, F., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., Von Zglinicki, T., et al. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature, 426, 194–8.

    Article  PubMed  CAS  Google Scholar 

  • Daniel, J. A., Pellegrini, M., Lee, B. S., Guo, Z., Filsuf, D., Belkina, N. V., et al. (2012). Loss of ATM kinase activity leads to embryonic lethality in mice. The Journal of Cell Biology, 198(3), 295–304.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Daniel, R., Ramcharan, J., Rogakou, E., Taganov, K. D., Greger, J. G., Bonner, W., et al. (2004). Histone H2AX is phosphorylated at sites of retroviral DNA integration but is dispensable for postintegration repair. The Journal of Biological Chemistry, 279(44), 45810–4.

    Article  PubMed  CAS  Google Scholar 

  • Dixon, J. R., Jung, I., Selvaraj, S., Shen, Y., Antosiewicz-Bourget, J. E., Lee, A. Y., et al. (2015). Chromatin architecture reorganization during stem cell differentiation. Nature, 518(7539), 331–6.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Downs, J. A., & Jackson, S. P. (2004). A means to a DNA end: The many roles of Ku. Nature Reviews Molecular Cell Biology, 5, 367–78.

    Article  PubMed  CAS  Google Scholar 

  • Dunham, I., Kundaje, A., Aldred, S. F., Collins, P. J., Davis, C. A., Doyle, F., et al. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 57–74.

    Article  CAS  Google Scholar 

  • Evans, J. W., Chernikova, S. B., Kachnic, L. A., Banath, J. P., Sordet, O., Delahoussaye, Y. M., et al. (2008). Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells. Cancer Research, 68(15), 257–65.

    Article  PubMed  CAS  Google Scholar 

  • Ewald, B., Sampath, D., & Plunkett, W. (2007). H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation. Molecular Cancer Therapeutics, 6(4), 1239–48.

    Article  PubMed  CAS  Google Scholar 

  • Ewald, B., Sampath, D., & Plunkett, W. (2008). Nucleoside analogs: Molecular mechanisms signaling cell death. Oncogene, 27(50), 6522–37.

    Article  PubMed  CAS  Google Scholar 

  • Falck, J., Coates, J., & Jackson, S. P. (2005). Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature, 434(March), 605–11.

    Article  PubMed  CAS  Google Scholar 

  • Fandy, T. E., Herman, J. G., Kerns, P., Jiemjit, A., Sugar, E. A., Choi, S. H., et al. (2009). Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood, 114, 2764–73.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Fernandez-Capetillo, O., Lee, A., Nussenzweig, M., & Nussenzweig, A. (2004). H2AX: The histone guardian of the genome. DNA Repair (Amst), 3, 959–67.

    Article  CAS  Google Scholar 

  • Fernandez-Capetillo, O., Liebe, B., Scherthan, H., & Nussenzweig, A. (2003). H2AX regulates meiotic telomere clustering. Journal of Cell Biology, 163, 15–20.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., et al. (2009). Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The New England Journal of Medicine, 361, 123–34.

    Article  PubMed  CAS  Google Scholar 

  • Furuta, T., Takemura, H., Liao, Z.-Y., Aune, G. J., Redon, C., Sedelnikova, O. A., et al. (2003). Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. The Journal of Biological Chemistry, 278(22), 20303–12.

    Article  PubMed  CAS  Google Scholar 

  • Iozzo, P., Holmes, M., Schmidt, M. V., Cirulli, F., Guzzardi, M. A., Berry, A., et al. (2014). Developmental ORIgins of healthy and unhealthy AgeiNg: The role of maternal obesity: Introduction to DORIAN. Obesity Facts, 7, 130–51.

    Article  PubMed  CAS  Google Scholar 

  • Ivashkevich, A., Redon, C. E., Nakamura, A. J., Martin, R. F., & Martin, O. A. (2012). Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research. Cancer Letters, 327, 123–33.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Jenuwein, T., & Allis, C. D. (2001). Translating the histone code. Science, 293(5532), 1074–80.

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi, J., Antoccia, A., Tauchi, H., Matsuura, S., & Komatsu, K. (2004). NBS1 and its functional role in the DNA damage response. DNA Repair (Amst), 3, 855–61.

    Article  CAS  Google Scholar 

  • Koren, A., Thurman, R., Sandstrom, R., Lawrence, M. S., Reynolds, A., Polak, P., et al. (2015). Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature, 518(0316), 360–4.

    PubMed Central  PubMed  Google Scholar 

  • Kurz, E. U., Douglas, P., & Lees-Miller, S. P. (2004). Doxorubicin activates ATM-dependent phosphorylation of multiple downstream targets in part through the generation of reactive oxygen species. The Journal of Biological Chemistry, 279(51), 53272–81.

    Article  PubMed  CAS  Google Scholar 

  • Lu, C., Zhu, F., Cho, Y. Y., Tang, F., Zykova, T., & Ma, W. Y. (2006). Cell apoptosis: Requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3. Molecular Cell, 23(1), 121–32.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Luger, K., Mäder, A. W., Richmond, R. K., Sargent, D. F., & Richmond, T. J. (1997). Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature, 389(6648), 251–60.

    Article  PubMed  CAS  Google Scholar 

  • Lukas, C., Melander, F., Stucki, M., Falck, J., Bekker-Jensen, S., Goldberg, M., et al. (2004). Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. EMBO Journal, 23(13), 2674–83.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Mahadevaiah, S. K., Turner, J. M., Baudat, F., Rogakou, E. P., de Boer, P., Blanco-Rodríguez, J., et al. (2001). Recombinational DNA double-strand breaks in mice precede synapsis. Nature Genetics, 27(3), 271–6.

    Article  PubMed  CAS  Google Scholar 

  • Matsuzaki, K., Harada, A., Takeiri, A., Tanaka, K., & Mishima, M. (2010). Whole cell-ELISA to measure the γH2AX response of six aneugens and eight DNA-damaging chemicals. Mutation Research: Genetic Toxicology and Environmental Mutagenesis, 700(1–2), 71–9.

    Article  CAS  Google Scholar 

  • McKinnon, P. J. (2004). ATM and ataxia telangiectasia. EMBO Reports, 5(8), 772–6.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Meng, F., Evans, J. W., Bhupathi, D., Banica, M., Lan, L., Lorente, G., et al. (2012). Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Molecular Cancer Therapeutics, 11, 740–51.

    Article  PubMed  CAS  Google Scholar 

  • Mirzoeva, O. K., Kawaguchi, T., & Pieper, R. O. (2006). The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity. Molecular Cancer Therapeutics, 5(11), 2757–66.

    Article  PubMed  CAS  Google Scholar 

  • Moroni, M., Maeda, D., Whitnall, M. H., Bonner, W. M., & Redon, C. E. (2013). Evaluation of the gamma-H2AX assay for radiation biodosimetry in a swine model. International Journal of Molecular Sciences, 14, 14119–35.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Murata, M., Thanan, R., Ma, N., & Kawanishi, S. (2012). Role of nitrative and oxidative DNA damage in inflammation-related carcinogenesis (Figure 1). Journal of Biomedicine & Biotechnology, 2012, 623019.

    Article  CAS  Google Scholar 

  • Niedernhofer, L. J., Odijk, H., Budzowska, M., van Drunen, E., Maas, A., Theil, A. F., et al. (2004). The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Molecular and Cellular Biology, 24(13), 5776–87.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Norris, R. E., & Adamson, P. C. (2012). Challenges and opportunities in childhood cancer drug development. Nature Reviews Cancer, 12(11), 776–82.

    Article  PubMed  CAS  Google Scholar 

  • Olive, P. L., & Banáth, J. P. (2009). Kinetics of H2AX phosphorylation after exposure to cisplatin. Cytometry. Part B, Clinical Cytometry, 76(2), 79–90.

    Article  PubMed  CAS  Google Scholar 

  • Orta, M. L., Calderón-Montaño, J. M., Domínguez, I., Pastor, N., Burgos-Morón, E., López-Lázaro, M., et al. (2013). 5-Aza-2′-deoxycytidine causes replication lesions that require Fanconi anemia-dependent homologous recombination for repair. Nucleic Acids Research, 41(11), 5827–36.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Palii, S. S., Van Emburgh, B. O., Sankpal, U. T., Brown, K. D., & Robertson, K. D. (2008). DNA methylation inhibitor 5-Aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Molecular and Cellular Biology, 28(2), 752–71.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Pang, B., Qiao, X., Janssen, L., Velds, A., Groothuis, T., Kerkhoven, R., et al. (2013). Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nature Communications, 4, 1908.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Panier, S., & Boulton, S. J. (2014). Double-strand break repair: 53BP1 comes into focus. Nature Reviews Molecular Cell Biology, 15(December), 7–18.

    PubMed  CAS  Google Scholar 

  • Parsels Leslie, A., Morgan, M. A., Tanska, D. M., Parsels, J. D., Palmer, B. D., Booth, R. J., et al. (2009). Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells. Molecular Cancer Therapeutics, 8(1), 45–54.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Patel, A. G., De Lorenzo, S. B., Flatten, K. S., Poirier, G. G., & Kaufmann, S. H. (2012). Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clinical Cancer Research, 18(14), 1655–62.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Paull, T. T., Rogakou, E. P., Yamazaki, V., Kirchgessner, C. U., Gellert, M., & Bonner, W. M. (2000). A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Current Biology, 10(15), 886–95.

    Article  PubMed  CAS  Google Scholar 

  • Petitprez, A., Poindessous, V., Ouaret, D., Regairaz, M., Bastian, G., Guérin, E., et al. (2013). Acquired irinotecan resistance is accompanied by stable modifications of cell cycle dynamics independent of MSI status. International Journal of Oncology, 42, 1644–53.

    PubMed  CAS  Google Scholar 

  • Rao, V. A., Agama, K., Holbeck, S., & Pommier, Y. (2007). Batracylin (NSC 320846), a dual inhibitor of DNA topoisomerases I and II induces histone γ-H2AX as a biomarker of DNA damage. Cancer Research, 67, 9971–9.

    Article  PubMed  CAS  Google Scholar 

  • Redon, C. E., Nakamura, A. J., Gouliaeva, K., Rahman, A., Blakely, W. F., & Bonner, W. M. (2010a). The use of gamma-H2AX as a biodosimeter for total-body radiation exposure in non-human primates. PLoS One, 5(11), e15544.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Redon, C. E., Nakamura, A. J., Zhang, Y.-W., Ji, J. J., Bonner, M. W., Kinders, R. J., et al. (2010b). Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers. Clinical Cancer Research, 16(18), 4532–42.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Redon, C. E., Weyemi, U., Parekh, P. R., Huang, D., Burrell, A. S., & Bonner, W. M. (2012). γ-H2AX and other histone post-translational modifications in the clinic. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1819(7), 743–56.

    Article  CAS  Google Scholar 

  • Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., et al. (2015). Integrative analysis of 111 reference human epigenomes. Nature, 518, 317–30.

    Article  PubMed Central  CAS  Google Scholar 

  • Robison, L. L., & Hudson, M. M. (2014). Survivors of childhood and adolescent cancer: Life-long risks and responsibilities. Nature Reviews Cancer, 14(1), 61–70.

    Article  PubMed  CAS  Google Scholar 

  • Rogakou, E. P., Boon, C., Redon, C. E., & Bonner, M. W. (1999). Megabase chromatin domains involved in DNA double-strand breaks in vivo. The Journal of Cell Biology, 146(5), 905–16.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Rogakou, E. P., Nieves-Neira, W., Boon, C., Pommier, Y., & Bonner, M. W. (2000). Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. The Journal of Biological Chemistry, 275(13), 9390–5.

    Article  PubMed  CAS  Google Scholar 

  • Rogakou, E. P., Pilch, D. R., Orra, H., Ivanova, V. S., & Bonner, M. W. (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. The Journal of Biological Chemistry, 273(10), 5858–68.

    Article  PubMed  CAS  Google Scholar 

  • Roh, D. S., Cook, A. L., Rhee, S. S., Joshi, A., Kowalski, R., Dhaliwal, D. K., et al. (2008). DNA cross-linking, double-strand breaks, and apoptosis in corneal endothelial cells after a single exposure to mitomycin C. Investigative Ophthalmology & Visual Science, 49(11), 4837–43.

    Article  Google Scholar 

  • Romanoski, C. E., Glass, C. K., Stunnenberg, H. G., Wilson, L., & Almouzni, G. (2015). Epigenomics: Roadmap for regulation. Nature, 518(7539), 314–316.

    Google Scholar 

  • Rübe, C. E., Fricke, A., Schneider, R., Simon, K., Kühne, M., Fleckenstein, J., et al. (2015). DNA repair alterations in children with pediatric malignancies: Novel opportunities to identify patients at risk for high-grade toxicities. International Journal of Radiation Oncology Biology Physics, 78(2), 359–69.

    Article  CAS  Google Scholar 

  • Santos, M. A., Faryabi, R. B., Ergen, A. V., Day, A. M., Malhowski, A., Canela, A., et al. (2014). DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier. Nature, 514, 107–11.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Scully, R., & Xie, A. (2013). Double strand break repair functions of histone H2AX. Mutation Research, 750, 5–14.

    Article  PubMed  CAS  Google Scholar 

  • Sedelnikova, O. A., Horikawa, I., Zimonjic, D. B., Popescu, N. C., Bonner, W. M., & Barrett, J. C. (2004). Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nature Cell Biology, 6(1), 168–70.

    Article  PubMed  CAS  Google Scholar 

  • Sedelnikova, O., Rogakou, E. P., Panyutin, I. G., & Bonner, W. M. (2002). Quantitative detection of 125IdU-induced DNA double-strand breaks with γ-H2AX antibody. Radiation Research, 158, 486–92.

    Article  PubMed  CAS  Google Scholar 

  • Seedhouse, C., Grundy, M., Shang, S., Ronan, J., Pimblett, H., Russell, N., et al. (2009). Impaired S-phase arrest in acute myeloid leukemia cells with a FLT3 internal tandem duplication treated with clofarabine. Clinical Cancer Research, 15(23), 7291–8.

    Article  PubMed  CAS  Google Scholar 

  • Shah, K., Cornelissen, B., Kiltie, A. E., & Vallis, K. A. (2013). Can H2AX be used to personalise cancer treatment? Current Molecular Medicine, 13, 1–12.

    Article  CAS  Google Scholar 

  • Shen, Y., Rehman, F. L., Feng, Y., Boshuizen, J., Bajrami, I., Elliott, R., et al. (2013). BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clinical Cancer Research, 19, 5003–15.

    Article  PubMed  CAS  Google Scholar 

  • Sinha, G. (2014). Downfall of iniparib: A PARP inhibitor that doesn’t inhibit PARP after all. Journal of the National Cancer Institute, 106, 1–2.

    Google Scholar 

  • Solier, S., & Pommier, Y. (2009). The apoptotic ring: A novel entity with phosphorylated histones H2AX and H2B and activated DNA damage response kinases. Cell Cycle, 8, 1853–9.

    Article  PubMed  CAS  Google Scholar 

  • Song, H., Hedayati, M., Hobbs, R. F., Shao, C., Bruchertseifer, F., Morgenstern, A., et al. (2013). Targeting aberrant DNA double-strand break repair in triple-negative breast cancer with alpha-particle emitter radiolabeled anti-EGFR antibody. Molecular Cancer Therapeutics, 12(10), 2043–54.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Strahl, B. D., & Allis, C. D. (2000). The language of covalent histone modifications. Nature, 403(January), 41–5.

    Article  PubMed  CAS  Google Scholar 

  • Stucki, M., & Jackson, S. P. (2004). MDC1/NFBD1: A key regulator of the DNA damage response in higher eukaryotes. DNA Repair (Amst), 3, 953–7.

    Article  CAS  Google Scholar 

  • Sun, J. D., Liu, Q., Wang, J., Ahluwalia, D., Ferraro, D., Wang, Y., et al. (2012). Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clinical Cancer Research, 18(3), 758–70.

    Article  PubMed  CAS  Google Scholar 

  • Takai, H., Smogorzewska, A., & De Lange, T. (2003). DNA damage foci at dysfunctional telomeres. Current Biology, 13, 1549–56.

    Article  PubMed  CAS  Google Scholar 

  • Tanaka, T., Halicka, H. D., Huang, X., Traganos, F., & Darzynkiewicz, Z. (2006). Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants. Cell Cycle, 5(17), 1940–5.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Thierry-Chef, I., Dabin, J., Friberg, E. G., Hermen, J., Istad, T. S., Jahnen, N., et al. (2013). Assessing organ doses from paediatric CT scans-A novel approach for an epidemiology study (the EPI-CT study). International Journal of Environmental Research and Public Health, 10, 717–28.

    Article  PubMed Central  PubMed  Google Scholar 

  • Trivedi, R. N., Almeida, K. H., Fornsaglio, J. L., Schamus, S., & Sobol, R. W. (2005). The role of base excision repair in the sensitivity and resistance to temozolomide-mediated cell death. Cancer Research, 14, 6394–401.

    Article  Google Scholar 

  • Van Attikum, H., & Gasser, S. M. (2005). The histone code at DNA breaks: A guide to repair? Nature Reviews Molecular Cell Biology, 6, 757–65.

    Article  PubMed  CAS  Google Scholar 

  • Van Vuurden, D. G., Hulleman, E., Meijer, O. L. M., Wedekind, L. E., Kool, M., Witt, H., et al. (2011). PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation. Oncotarget, 2(12), 984–96.

    Article  PubMed Central  PubMed  Google Scholar 

  • Williamson, E. A., Wray, J. W., Bansal, P., & Hromas, R. (2012). Overview for the histone codes for DNA repair. Progress in Molecular Biology and Translational Science, 110, 207–27.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Yan, L., Bulgar, A., Miao, Y., Mahajan, V., Donze, J. R., Gerson, S. L., et al. (2007). Combined treatment with temozolomide and methoxyamine: Blocking apurininc/pyrimidinic site repair coupled with targeting topoisomerase II?? Clinical Cancer Research, 13(14), 1532–9.

    Article  PubMed  CAS  Google Scholar 

  • Yan, T., Seo, Y., Schupp, J. E., Zeng, X., Desai, A. B., & Kinsella, T. J. (2006). Methoxyamine potentiates iododeoxyuridine-induced radiosensitization by altering cell cycle kinetics and enhancing senescence. Molecular Cancer Therapeutics, 5(April), 893–902.

    Article  PubMed  CAS  Google Scholar 

  • Yin, B., Savic, V., Juntilla, M. M., Bredemeyer, A. L., Yang-Iott, K. S., & Helmink, B. (2009). a, et al. Histone H2AX stabilizes broken DNA strands to suppress chromosome breaks and translocations during V(D)J recombination. Journal of Experimental Medicine, 206(12), 2625–39.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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Correspondence to Emmy P. Rogakou PhD .

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Abbreviations

Abbreviations

AID:

Activation-induced cytidine deaminase

ATM:

Ataxia telangiectasia mutated

CAD:

Caspase-activated DNase

CSR:

Class switch recombination

DSB:

Double-stranded break

dU:

Deoxy-uracil

HDAC:

Histone deacetylase

NHEJ:

Nonhomologous End-Joining

PARP:

ADP ribose polymerases

Topo I:

Topoisomerase I

Topo II:

Topoisomerase II

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Rogakou, E.P., Papadakis, V., Chrousos, G.P. (2016). The Epigenetic Biomarker γH2AX: From Bench to Clinical Trials. In: Hollar, D. (eds) Epigenetics, the Environment, and Children’s Health Across Lifespans. Springer, Cham. https://doi.org/10.1007/978-3-319-25325-1_4

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