H2AX Is Required for Chromatin Remodeling and Inactivation of Sex Chromosomes in Male Mouse Meiosis

Abstract

During meiotic prophase in male mammals, the X and Y chromosomes condense to form a macrochromatin body, termed the sex, or XY, body, within which X- and Y-linked genes are transcriptionally repressed. The molecular basis and biological function of both sex body formation and meiotic sex chromosome inactivation (MSCI) are unknown. A phosphorylated form of H2AX, a histone H2A variant implicated in DNA repair, accumulates in the sex body in a manner independent of meiotic recombination-associated double-strand breaks. Here we show that the X and Y chromosomes of histone H2AX-deficient spermatocytes fail to condense to form a sex body, do not initiate MSCI, and exhibit severe defects in meiotic pairing. Moreover, other sex body proteins, including macroH2A1.2 and XMR, do not preferentially localize with the sex chromosomes in the absence of H2AX. Thus, H2AX is required for the chromatin remodeling and associated silencing in male meiosis.

Sex chromosomes, synapsis, and cohesins: a complex affair

“…It has been proposed that BRCA1 and ATR are targeted to unsynapsed AEs at late zygotene, and they are involved in triggering the process of meiotic sex chromosome inactivation (MSCI) (Turner et al 2004). Furthermore, ATR, a phosphoinositide-3-kinase-related kinase, also localizes in the chromatin of both sex chromosomes, where it could phosphorylate the histone variant H2AX, a necessary step for the initiation of MSCI (Fernandez-Capetillo et al 2003;Turner et al 2004;Bellani et al 2005). The immunolocalization of these two proteins reveals that ATR encompasses the modifications of AEs during pachytene and early diplotene, whereas BRCA1 does not (Fig.…”

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

“…These foci are essential in facilitating the assembly of repair factors, including Brca1 and the MRE11-RAD50-NBS1 complex, on damaged DNA (Paull et al, 2000;Celeste et al, 2002), and also aid in the transduction of DNA damage signals by binding to 53BP1 and MDC1 (FernandezCapetillo et al, 2002;Stewart et al, 2003). gH2AX foci also form at sites of physiological DSBs in lymphocytes and germ cells (Chen et al, 2000;Mahadevaiah et al, 2001;Petersen et al, 2001;Fernandez-Capetillo et al, 2003). Knocking out H2AX produces mice with immune deficiency and male infertility , while loss or reduction of H2AX compromises genome stability and facilitates tumorigenesis Bassing et al, 2003;Celeste et al, 2003).…”

CHFR is important for the survival of male premeiotic germ cells

“…5 In agreement with these important functions, meiosis in knockout mice for H2AX, MDC1, and ATM arrests before the onset of meiotic division. [6][7][8][9] Another group of DNA damage response proteins functions in spermiogenesis, during which haploid round spermatids elongate and compact their nucleus. It is believed that DNA damage occurs during this process.…”