BRCA1, Histone H2AX Phosphorylation, and Male Meiotic Sex Chromosome Inactivation

Abstract

In mammalian spermatogenesis, the X and Y chromosomes are transcriptionally silenced during the pachytene stage of meiotic prophase (meiotic sex chromosome inactivation, MSCI), forming a condensed chromatin domain termed the sex or XY body. The nucleosomal core histone H2AX is phosphorylated within the XY chromatin domain just prior to MSCI, and it has been hypothesized that this triggers the chromatin condensation and transcriptional repression. Here, we show that the kinase ATR localizes to XY chromatin at the onset of MSCI and that this localization is disrupted in mice with a mutant form of the tumor suppressor protein BRCA1. In the mutant pachytene cells, ATR is usually present at nonsex chromosomal sites, where it colocalizes with aberrant sites of H2AX phosphorylation; in these cells, there is MSCI failure. In rare pachytene cells, ATR does locate to XY chromatin, H2AX is then phosphorylated, a sex body forms, and MSCI ensues. These observations highlight an important role for BRCA1 in recruiting the kinase ATR to XY chromatin at the onset of MSCI and provide compelling evidence that it is ATR that phosphorylates H2AX and triggers MSCI.

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

“…This suggests a possible role for BRCA1 and BRCA2 in meiotic recombination, for which some functional evidence now exists [80]. (A role for BRCA1 in transcriptional silencing during meiosis is also likely [81,82].) Attempts to cultivate BRCA1 or BRCA2 null primary mammalian cells in vitro have been unsuccessful, perhaps reflecting the severity of the recombination defect in these cells.…”

“…This review has not touched upon the contributions of BRCA1 and BRCA2 to checkpoint functions [150][151][152], transcriptional regulation [153,154], gene silencing [81,82,155], telomere function [96] or (for BARD1) mRNA processing [156,157]. Both HR and non-HR functions of BRCA genes might account for the tissue specificity of cancer risk in BRCA gene mutation carriers [158] and the latter may be important modulators of the clinical phenotypes associated with BRCA gene inactivation.…”

Sex chromosomes, synapsis, and cohesins: a complex affair

“…However, during pachytene, their distribution is restricted to the unsynapsed regions of the sex chromosomes (Keegan et al 1996;Scully et al 1997;Moens et al 1999). 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).…”

“…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.…”

The X and Y chromosome in meiosis: how and why they keep silent

“…6 The phosphorylation of H2AX at the XY body is mediated by the checkpoint kinase ATR that can be visualized along the unsynapsed axes of X and Y from late zygotene onwards. 8 In their recent paper, Ichijima et al 4 reveal that the phosphorylation of H2AX occurs in two phases; first, it is restricted to the chromosomal axes, then the area extends, and H2AX also becomes phosphorylated in the surrounding chromatin loops. This second phase, when cH2AX spreads, depends on a protein named mediator of DNA damage checkpoint 1 (MDC1), and this function is required for transcriptional silencing of the sex chromosomes ( Figure 1).…”