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Reversal of Female Infertility by Chk2 Ablation Reveals the Oocyte DNA Damage Checkpoint Pathway

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Science  31 Jan 2014:
Vol. 343, Issue 6170, pp. 533-536
DOI: 10.1126/science.1247671

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Eggs Well Done

Germ cells can endure extensive DNA damage during their development. Programmed meiotic double-strand breaks (DSBs) are essential for proper segregation of chromosomes to oocytes and sperm. However, incomplete DSB repair by recombination activates a checkpoint that triggers cell death. Exogenous DNA damage is also lethal to oocytes via a highly sensitive checkpoint. Bolcun-Filas et al. (p. 533) show that the CHK2 kinase is a key component of both checkpoints in mouse oocytes. Deletion of Chk2 restored fertility to females that would otherwise be sterile because of a meiotic recombination mutation or radiation exposure.

Abstract

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.

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