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.
Turner
James M A
JM
Division of Stem Cell Biology and Developmental Genetics, Medical Research Council, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
Aprelikova
Olga
O
Xu
Xiaoling
X
Wang
Ruihong
R
Kim
Sangsoo
S
Chandramouli
Gadisetti V R
GV
Barrett
J Carl
JC
Burgoyne
Paul S
PS
Deng
Chu-Xia
CX
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D017931:DNA Primers; D019398:Genes, BRCA1 / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D049471:Pachytene Stage / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012730:Sex Chromosomes / Q000502:physiology*; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D017931:DNA Primers; D006657:Histones; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases