Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway.
Genetic errors in meiosis can lead to birth defects and spontaneous abortions. Checkpoint mechanisms of hitherto unknown nature eliminate oocytes with unrepaired DNA damage, causing recombination-defective mutant mice to be sterile. Here, we report that checkpoint kinase 2 (Chk2 or Chek2), is essential for culling mouse oocytes bearing unrepaired meiotic or induced DNA double-strand breaks (DSBs). Female infertility caused by a meiotic recombination mutation or irradiation was reversed by mutation of Chk2. Both meiotically programmed and induced DSBs trigger CHK2-dependent activation of TRP53 (p53) and TRP63 (p63), effecting oocyte elimination. These data establish CHK2 as essential for DNA damage surveillance in female meiosis and indicate that the oocyte DSB damage response primarily involves a pathway hierarchy in which ataxia telangiectasia and Rad3-related (ATR) signals to CHK2, which then activates p53 and p63.
Department of Biomedical Sciences, Cornell University, Ithaca, NY 14850, USA.
Ewelina
E
Bolcun-Filas
Vera D
VD
Rinaldi
Michelle E
ME
White
John C
JC
Schimenti
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007247:Infertility, Female / Q000235:genetics* / Q000473:pathology; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009865:Oocytes / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C523791:Trip13 protein, mouse