BRCA1, Histone H2AX Phosphorylation, and Male Meiotic Sex Chromosome Inactivation
pmid: 15589157
BRCA1, Histone H2AX Phosphorylation, and Male Meiotic Sex Chromosome Inactivation
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.
- National Cancer Institute United States
- National Institute of Health Pakistan
- Medical Research Council United Kingdom
- National Institute for Medical Research United Kingdom
- National Institutes of Health United States
Male, Sex Chromosomes, Agricultural and Biological Sciences(all), Biochemistry, Genetics and Molecular Biology(all), Reverse Transcriptase Polymerase Chain Reaction, Blotting, Western, Genes, BRCA1, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Chromatin Assembly and Disassembly, Immunohistochemistry, Histones, Mice, Mutation, Animals, Immunoprecipitation, Pachytene Stage, Phosphorylation, In Situ Hybridization, Fluorescence, DNA Primers, Oligonucleotide Array Sequence Analysis
Male, Sex Chromosomes, Agricultural and Biological Sciences(all), Biochemistry, Genetics and Molecular Biology(all), Reverse Transcriptase Polymerase Chain Reaction, Blotting, Western, Genes, BRCA1, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Chromatin Assembly and Disassembly, Immunohistochemistry, Histones, Mice, Mutation, Animals, Immunoprecipitation, Pachytene Stage, Phosphorylation, In Situ Hybridization, Fluorescence, DNA Primers, Oligonucleotide Array Sequence Analysis
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