Multiple facets of histone variant H2AX: a DNA double-strand-break marker with several biological functions

Abstract

In the last decade, many papers highlighted that the histone variant H2AX and its phosphorylation on Ser 139 (γH2AX) cannot be simply considered a specific DNA double-strand-break (DSB) marker with a role restricted to the DNA damage response, but rather as a ‘protagonist’ in different scenarios. This review will present and discuss an up-to-date view regarding the ‘non-canonical’ H2AX roles, focusing in particular on possible functional and structural parts in contexts different from the canonical DNA DSB response. We will present aspects concerning sex chromosome inactivation in male germ cells, X inactivation in female somatic cells and mitosis, but will also focus on the more recent studies regarding embryonic and neural stem cell development, asymmetric sister chromosome segregation in stem cells and cellular senescence maintenance. We will discuss whether in these new contexts there might be a relation with the canonical DNA DSB signalling function that could justify γH2AX formation. The authors will emphasize that, just as H2AX phosphorylation signals chromatin alteration and serves the canonical function of recruiting DSB repair factors, so the modification of H2AX in contexts other than the DNA damage response may contribute towards creating a specific chromatin structure frame allowing ‘non-canonical’ functions to be carried out in different cell types.

NovelHelicobacterspeciesH.japonicumisolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10−/−mice

“…When cells are exposed to ionizing radiation or DNA-damaging chemotherapeutic agents, DSBs are generated that rapidly result in the phosphorylation of histone H2A variant H2AX. Because phosphorylation of H2AX at Ser 139 (γ-H2AX) correlates well with each DSB, it is the most sensitive marker that can be used to examine the DNA damage produced and the subsequent repair of the DNA lesion (30,31). We used immunofluorescence staining γ-H2AX to detect DSB in the event of H.japonicum infection.…”

TSSK6 is required for γH2AX formation and the histone-to-protamine transition during spermiogenesis

“…γH2AX has also been implicated in chromatin remodeling that takes place during several other biological processes, such as male sex chromosome inactivation in germ cells, X chromosome inactivation in somatic cells, asymmetric sister chromosome segregation in stem cells and cellular senescence maintenance in fibroblasts (Turinetto and Giachino, 2015). Targeted deletion of histone H2AX in mice results in male, but not female, infertility due to failure of sex-body formation and meiotic sex chromosome inactivation (MSCI) in spermatocytes (Celeste et al, 2002;Fernandez-Capetillo et al, 2003).…”

Residual γH2AX foci after ex vivo irradiation of patient samples with known tumour-type specific differences in radio-responsiveness

“…H2AX, has attracted particular attention. Upon irradiation or other exogenous stress, numerous molecules of H2AX are rapidly phosphorylated at the flanking sites of chromatin where DSBs have been induced forming the so-called cH2AX nuclear foci [21][22][23][24][25][26][27][28][29][30][31]. The fact that phosphorylation remains at the sites of DSBs until the end of repair processes before the foci are dephosphorylated [32][33][34][35][36] facilitates the study of foci disappearance along with the quantitative evaluation of residual DSBs [20,21,23,29,[37][38][39][40][41].…”

“…The fact that phosphorylation remains at the sites of DSBs until the end of repair processes before the foci are dephosphorylated [32][33][34][35][36] facilitates the study of foci disappearance along with the quantitative evaluation of residual DSBs [20,21,23,29,[37][38][39][40][41]. In several studies both these endpoints have been correlated with cellular radiation sensitivity in vitro and in vivo either in tumour or normal tissue samples [20,21,23,28,29,31,37,39,41,42]. Taking together, the cH2AX assay is simple, sensitive and straightforward method to quantify DSBs in cells and tissues and therefore promising for translation into clinical trials.…”