Structural damage to meiotic chromosomes impairs DNA recombination and checkpoint control in mammalian oocytes.
Meiosis in human oocytes is a highly error-prone process with profound effects on germ cell and embryo development. The synaptonemal complex protein 3 (SYCP3) transiently supports the structural organization of the meiotic chromosome axis. Offspring derived from murine Sycp3(-)(/)(-) females die in utero as a result of aneuploidy. We studied the nature of the proximal chromosomal defects that give rise to aneuploidy in Sycp3(-)(/)(-) oocytes and how these errors evade meiotic quality control mechanisms. We show that DNA double-stranded breaks are inefficiently repaired in Sycp3(-)(/)(-) oocytes, thereby generating a temporal spectrum of recombination errors. This is indicated by a strong residual gammaH2AX labeling retained at late meiotic stages in mutant oocytes and an increased persistence of recombination-related proteins associated with meiotic chromosomes. Although a majority of the mutant oocytes are rapidly eliminated at early postnatal development, a subset with a small number of unfinished crossovers evades the DNA damage checkpoint, resulting in the formation of aneuploid gametes.
Wang
Hong
H
Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Höög
Christer
C
D000782:Aneuploidy; D000818:Animals; D018797:Cell Cycle Proteins; D002869:Chromosome Aberrations / Q000196:embryology; D019457:Chromosome Breakage / Q000235:genetics*; D002875:Chromosomes / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D018816:Genes, cdc / Q000502:physiology*; D006657:Histones / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism* / Q000648:ultrastructure; D011995:Recombination, Genetic / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C490062:Sycp3 protein, mouse; C475961:gamma-H2AX protein, mouse