How DNA‐Damage Machinery Protects the Genomes of Mouse Oocytes

Abstract

During meiosis hundreds of endogenously induced DNA double stranded breaks (DSB) are made by the SPO11 endonuclease in order to assure homologous chromosome pairing (synapsis) and their proper segregation. Because DSBs are potentially mutagenic, quality control mechanisms are in place to guarantee that they are all repaired, preferentially by interhomolog recombination, otherwise apoptosis is induced. It is currently accepted that this “pachytene checkpoint” senses DSB repair and synapsis by independent mechanisms. However, we have experimental evidence that oocytes defective for either DNA repair or synapsis are both eliminated by a canonical DNA damage response checkpoint pathway (dependent upon signaling of the CHK2 kinase to downstream effectors p53 and p63). During the first meiotic division, mechanisms are in place to inhibit the DNA‐repair machinery from using the sister chromatid as recombination repair donors, making the homologous chromosome the substrate of choice. Whereas this block to sister chromatid repair of DSBs assures interhomolog (IH) recombination, it also prevents the chromosomes that fail to undergo IH repair from repairing residual DSBs. Here, we present evidence consistent with a model whereby asynaptic oocytes accumulate SPO11‐independent DSBs, and are eliminated via CHK2 activation.