Phosphorylation of histone H2A.X as a DNA‑associated biomarker (Review)

Stope,Matthias B.

doi:10.3892/wasj.2021.102

Phosphorylation of histone H2A.X as a DNA‑associated biomarker (Review)

Authors:
- Matthias B. Stope
View Affiliations

Affiliations: Department of Gynecology and Gynecological Oncology, University Hospital Bonn, 53127 Bonn, Germany
Published online on: April 21, 2021 https://doi.org/10.3892/wasj.2021.102
Article Number: 31
Copyright: © Stope . This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The complex genomic structure of eukaryotic cells is primarily achieved by the binding of DNA to histones. Different members of the histone families form a complex with genomic DNA and, as a nucleosome, constitute the functional unit of chromatin. In addition to their structural functionality, histones are also involved in other molecular mechanisms, such as DNA damage recognition and repair. A very important factor of DNA damage management is the histone H2A.X. The phosphorylation of H2A.X initiates various processes of the DNA repair systems and plays significant roles in cellular regulation. The H2A.X phosphorylation status represents a central sum parameter for genome integrity and allows conclusions to be drawn about DNA‑associated processes in cells and tissues. As a biomarker for DNA damage and genotoxicity, as well as a clinical marker for radiotherapy outcome, drug efficacy and tissue regeneration, the H2A.X phosphorylation status represents an effective biomarker for current and future biomedical applications. The present brief review article provides an overview of the various molecular functions and cellular events in which the phosphorylation of histone H2A.X can occur.

View Figures

View References

1	Biterge B and Schneider R: Histone variants: Key players of chromatin. Cell Tissue Res. 356:457–466. 2014.PubMed/NCBI View Article : Google Scholar
2	Luger K, Mäder AW, Richmond RK, Sargent DF and Richmond TJ: Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature. 389:251–260. 1997.PubMed/NCBI View Article : Google Scholar
3	Singh RK, Paik J and Gunjan A: Generation and management of excess histones during the cell cycle. Front Biosci. 14:3145–3158. 2009.PubMed/NCBI View Article : Google Scholar
4	Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K and Bonner W: Histone H2A variants H2AX and H2AZ. Curr Opin Genet Dev. 12:162–169. 2002.PubMed/NCBI View Article : Google Scholar
5	Kuo LJ and Yang LX: Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo. 22:305–309. 2008.PubMed/NCBI
6	Sharma A, Singh K and Almasan A: Histone H2AX phosphorylation: A marker for DNA damage. Methods Mol Biol. 920:613–626. 2012.PubMed/NCBI View Article : Google Scholar
7	Varvara PV, Karaolanis G, Valavanis C, Stanc G, Tzaida O, Trihia H, Patapis P, Dimitroulis D and Perrea D: gamma-H2AX: A potential biomarker in breast cancer. Tumour Biol: Sep 25, 2019 (Epub ahead of print). doi: 10.1177/1010428319878536.
8	Johnson DP, Chandrasekharan MB, Dutreix M and Bhaskara S: Targeting DNA repair and chromatin crosstalk in cancer therapy. Cancers (Basel). 13(381)2021.PubMed/NCBI View Article : Google Scholar
9	Stiff T, O'Driscoll M, Rief N, Iwabuchi K, Löbrich M and Jeggo PA: ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res. 64:2390–2396. 2004.PubMed/NCBI View Article : Google Scholar
10	House NC, Koch MR and Freudenreich CH: Chromatin modifications and DNA repair: Beyond double-strand breaks. Front Genet. 5(296)2014.PubMed/NCBI View Article : Google Scholar
11	Ambekar SS, Hattur SS and Bule PB: DNA: Damage and repair mechanisms in humans. Glob J Pharm Pharm Sci. 3(555613)2018.
12	Rogakou EP, Boon C, Redon C and Bonner WM: Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol. 146:905–916. 1999.PubMed/NCBI View Article : Google Scholar
13	Osipov AN, Pustovalova M, Grekhova A, Eremin P, Vorobyova N, Pulin A, Zhavoronkov A, Roumiantsev S, Klokov DY and Eremin I: Low doses of X-rays induce prolonged and ATM-independent persistence of γH2AX foci in human gingival mesenchymal stem cells. Oncotarget. 6:27275–27287. 2015.PubMed/NCBI View Article : Google Scholar
14	Halicka HD, Huang X, Traganos F, King MA, Dai W and Darzynkiewicz Z: Histone H2AX phosphorylation after cell irradiation with UV-B: Relationship to cell cycle phase and induction of apoptosis. Cell Cycle. 4:339–345. 2005.PubMed/NCBI
15	Parsels LA, Parsels JD, Tanska DM, Maybaum J, Lawrence TS and Morgan MA: The contribution of DNA replication stress marked by high-intensity, pan-nuclear γH2AX staining to chemosensitization by CHK1 and WEE1 inhibitors. Cell Cycle. 17:1076–1086. 2018.PubMed/NCBI View Article : Google Scholar
16	Xiao H, Li TK, Yang J-M and Liu LF: Acidic pH induces topoisomerase II-mediated DNA damage. Proc Natl Acad Sci USA. 100:5205–5210. 2003.PubMed/NCBI View Article : Google Scholar
17	Kaneko H, Igarashi K, Kataoka K and Miura M: Heat shock induces phosphorylation of histone H2AX in mammalian cells. Biochem Biophys Res Commun. 328:1101–1106. 2005.PubMed/NCBI View Article : Google Scholar
18	Banáth JP and Olive PL: Expression of phosphorylated histone H2AX as a surrogate of cell killing by drugs that create DNA double-strand breaks. Cancer Res. 63:4347–4350. 2003.PubMed/NCBI
19	Kiziltepe T, Hideshima T, Catley L, Raje N, Yasui H, Shiraishi N, Okawa Y, Ikeda H, Vallet S, Pozzi S, et al: 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells. Mol Cancer Ther. 6:1718–1727. 2007.PubMed/NCBI View Article : Google Scholar
20	Guo Z, Kozlov S, Lavin MF, Person MD and Paull TT: ATM activation by oxidative stress. Science. 330:517–521. 2010.PubMed/NCBI View Article : Google Scholar
21	Li Z, Owonikoko TK, Sun SY, Ramalingam SS, Doetsch PW, Xiao ZQ, Khuri FR, Curran WJ and Deng X: c-Myc suppression of DNA double-strand break repair. Neoplasia. 14:1190–1202. 2012.PubMed/NCBI View Article : Google Scholar
22	Ewald B, Sampath D and Plunkett W: H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation. Mol Cancer Ther. 6:1239–1248. 2007.PubMed/NCBI View Article : Google Scholar
23	Williamson J, Hughes CM, Burke G and Davison GW: A combined γ-H2AX and 53BP1 approach to determine the DNA damage-repair response to exercise in hypoxia. Free Radic Biol Med. 154:9–17. 2020.PubMed/NCBI View Article : Google Scholar
24	Sedelnikova OA, Horikawa I, Zimonjic DB, Popescu NC, Bonner WM and Barrett JC: Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol. 6:168–170. 2004.PubMed/NCBI View Article : Google Scholar
25	Bekeschus S, Schütz CS, Niessner F, Wende K, Weltmann KD, Gelbrich N, von Woedtke T, Schmidt A and Stope MB: Elevated H2AX phosphorylation observed with kINPen plasma treatment is not caused by ROS-mediated DNA damage but is the consequence of apoptosis. Oxid Med Cell Longev. 2019(8535163)2019.PubMed/NCBI View Article : Google Scholar
26	Kulashreshtha M, Mehta IS, Kumar P and Rao BJ: Chromosome territory relocation during DNA repair requires nuclear myosin 1 recruitment to chromatin mediated by γ-H2AX signaling. Nucleic Acids Res. 44:8272–8291. 2016.PubMed/NCBI View Article : Google Scholar
27	Goutham HV, Mumbrekar KD, Vadhiraja BM, Fernandes DJ, Sharan K, Kanive Parashiva G, Kapaettu S and Bola Sadashiva SR: DNA double-strand break analysis by γ-H2AX foci: A useful method for determining the overreactors to radiation-induced acute reactions among head-and-neck cancer patients. Int J Radiat Oncol Biol Phys. 84:e607–e612. 2012.PubMed/NCBI View Article : Google Scholar
28	Sedelnikova OA, Rogakou EP, Panyutin IG and Bonner WM: Quantitative detection of (125)IdU-induced DNA double-strand breaks with gamma-H2AX antibody. Radiat Res. 158:486–492. 2002.PubMed/NCBI View Article : Google Scholar
29	Tomita M: Involvement of DNA-PK and ATM in radiation- and heat-induced DNA damage recognition and apoptotic cell death. J Radiat Res (Tokyo). 51:493–501. 2010.PubMed/NCBI View Article : Google Scholar
30	Fernandez-Capetillo O, Lee A, Nussenzweig M and Nussenzweig A: H2AX: The histone guardian of the genome. DNA Repair (Amst). 3:959–967. 2004.PubMed/NCBI View Article : Google Scholar
31	Li X, Nan A, Xiao Y, Chen Y and Lai Y: PP2A-B56є complex is involved in dephosphorylation of γ-H2AX in the repair process of CPT-induced DNA double-strand breaks. Toxicology. 331:57–65. 2015.PubMed/NCBI View Article : Google Scholar
32	Tu WZ, Li B, Huang B, Wang Y, Liu XD, Guan H, Zhang SM, Tang Y, Rang WQ and Zhou PK: γH2AX foci formation in the absence of DNA damage: Mitotic H2AX phosphorylation is mediated by the DNA-PKcs/CHK2 pathway. FEBS Lett. 587:3437–3443. 2013.PubMed/NCBI View Article : Google Scholar
33	Miller KM and Jackson SP: Histone marks: Repairing DNA breaks within the context of chromatin. Biochem Soc Trans. 40:370–376. 2012.PubMed/NCBI View Article : Google Scholar
34	Zhao H, Halicka HD, Garcia J, Li J and Darzynkiewicz Z: ATM activation and H2AX phosphorylation induced by genotoxic agents assessed by flow- and laser scanning cytometry. Methods Mol Biol. 1599:183–196. 2017.PubMed/NCBI View Article : Google Scholar
35	Hanasoge S and Ljungman M: H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase. Carcinogenesis. 28:2298–2304. 2007.PubMed/NCBI View Article : Google Scholar
36	Park E-J, Chan DW, Park J-H, Oettinger MA and Kwon J: DNA-PK is activated by nucleosomes and phosphorylates H2AX within the nucleosomes in an acetylation-dependent manner. Nucleic Acids Res. 31:6819–6827. 2003.PubMed/NCBI View Article : Google Scholar
37	Kinner A, Wu W, Staudt C and Iliakis G: Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res. 36:5678–5694. 2008.PubMed/NCBI View Article : Google Scholar
38	Kim ST, Lim DS, Canman CE and Kastan MB: Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem. 274:37538–37543. 1999.PubMed/NCBI View Article : Google Scholar
39	Zhang F and Gong Z: Regulation of DNA double-strand break repair pathway choice: A new focus on 53BP1. J Zhejiang Univ Sci B. 22:38–46. 2021.PubMed/NCBI View Article : Google Scholar
40	Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M and Bonner WM: A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 10:886–895. 2000.PubMed/NCBI View Article : Google Scholar
41	Kang J, Ferguson D, Song H, Bassing C, Eckersdorff M, Alt FW and Xu Y: Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression. Mol Cell Biol. 25:661–670. 2005.PubMed/NCBI View Article : Google Scholar
42	Tanaka T, Huang X, Jorgensen E, Gietl D, Traganos F, Darzynkiewicz Z and Albino AP: ATM activation accompanies histone H2AX phosphorylation in A549 cells upon exposure to tobacco smoke. BMC Cell Biol. 8(26)2007.PubMed/NCBI View Article : Google Scholar
43	Watters GP, Smart DJ, Harvey JS and Austin CA: H2AX phosphorylation as a genotoxicity endpoint. Mutat Res. 679:50–58. 2009.PubMed/NCBI View Article : Google Scholar
44	Bartkova J, Horejsí Z, Koed K, Krämer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, et al: DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 434:864–870. 2005.PubMed/NCBI View Article : Google Scholar
45	Olive PL and Banáth JP: Phosphorylation of histone H2AX as a measure of radiosensitivity. Int J Radiat Oncol Biol Phys. 58:331–335. 2004.PubMed/NCBI View Article : Google Scholar
46	Kawashima S, Kawaguchi N, Taniguchi K, Tashiro K, Komura K, Tanaka T, Inomata Y, Imai Y, Tanaka R, Yamamoto M, et al: γ-H2AX as a potential indicator of radiosensitivity in colorectal cancer cells. Oncol Lett. 20:2331–2337. 2020.PubMed/NCBI View Article : Google Scholar
47	Gorgoulis VG, Vassiliou L-VF, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, et al: Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 434:907–913. 2005.PubMed/NCBI View Article : Google Scholar
48	Palla VV, Karaolanis G, Katafigiotis I, Anastasiou I, Patapis P, Dimitroulis D and Perrea D: gamma-H2AX: Can it be established as a classical cancer prognostic factor? Tumour Biol: Mar 29, 2017 (Epub ahead of print). doi: 10.1177/1010428317695931.
49	Baritaud M, Cabon L, Delavallée L, Galán-Malo P, Gilles ME, Brunelle-Navas MN and Susin SA: AIF-mediated caspase-independent necroptosis requires ATM and DNA-PK-induced histone H2AX Ser139 phosphorylation. Cell Death Dis. 3(e390)2012.PubMed/NCBI View Article : Google Scholar
50	Mariotti LG, Pirovano G, Savage KI, Ghita M, Ottolenghi A, Prise KM and Schettino G: Use of the γ-H2AX assay to investigate DNA repair dynamics following multiple radiation exposures. PLoS One. 8(e79541)2013.PubMed/NCBI View Article : Google Scholar