Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation.
Chromosome synapsis during zygotene is a prerequisite for the timely homologous recombinational repair of meiotic DNA double-strand breaks (DSBs). Unrepaired DSBs are thought to trigger apoptosis during midpachytene of male meiosis if synapsis fails. An early pachytene response to asynapsis is meiotic silencing of unsynapsed chromatin (MSUC), which, in normal males, silences the X and Y chromosomes (meiotic sex chromosome inactivation [MSCI]). In this study, we show that MSUC occurs in Spo11-null mouse spermatocytes with extensive asynapsis but lacking meiotic DSBs. In contrast, three mutants (Dnmt3l, Msh5, and Dmc1) with high levels of asynapsis and numerous persistent unrepaired DSBs have a severely impaired MSUC response. We suggest that MSUC-related proteins, including the MSUC initiator BRCA1, are sequestered at unrepaired DSBs. All four mutants fail to silence the X and Y chromosomes (MSCI failure), which is sufficient to explain the midpachytene apoptosis. Apoptosis does not occur in mice with a single additional asynapsed chromosome with unrepaired meiotic DSBs and no disturbance of MSCI.
Mahadevaiah
Shantha K
SK
Division of Stem Cell Biology and Developmental Genetics, Medical Research Council National Institute for Medical Research, London NW7 1AA, England, UK.
Bourc'his
Déborah
D
de Rooij
Dirk G
DG
Bestor
Timothy H
TH
Turner
James M A
JM
Burgoyne
Paul S
PS
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D023902:Chromosome Pairing / Q000235:genetics*; D020090:Chromosome Segregation / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004706:Endodeoxyribonucleases; D004950:Esterases / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology*; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family / Q000235:genetics; D009154:Mutation / Q000235:genetics; D012730:Sex Chromosomes / Q000235:genetics*; D013087:Spermatids / Q000166:cytology / Q000378:metabolism; D013090:Spermatocytes / Q000166:cytology / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics*; D014998:Y Chromosome / Q000235:genetics; D000099257:Meiotic Recombination Protein SPO11
D019313:BRCA1 Protein; D004706:Endodeoxyribonucleases; D004950:Esterases; D000099257:Meiotic Recombination Protein SPO11