Genome integrity checkpoints in mammalian oogenesis

Preserving chromosome integrity and minimizing mutations are crucial in the germline to prevent infertility, pregnancy loss and birth defects. This is particularly important in mammalian females, who reach puberty with a limited pool of oocytes and therefore have a finite reproductive lifespan. The most complex and genome-threatening stage of oogenesis is meiosis, during which homologous chromosomes pair and segregate at the first meiotic division. This process depends on the formation of hundreds of genetically programmed double-strand breaks (DSBs), which promote homologous recombination repair (HRR) and thereby drive homolog pairing and synapsis. Genetic studies in model organisms have revealed the existence of quality control mechanisms, or checkpoints, that detect unrepaired DNA damage or defective synapsis and, in mammals, eliminate defective oocytes from the ovarian reserve. After nearly three decades of study, a model has emerged in which the DNA damage and synapsis checkpoints share extensive mechanistic overlap. Several DNA repair proteins and damage sensors have been co-opted to recognize unsynapsed chromatin and transmit these signals through canonical DNA damage response pathways to well-known downstream effectors including TRP53 (p53) and TAp63 that trigger oocyte death. This review summarizes the key studies that have defined genetic quality control mechanisms that act before and during oogenesis, underscoring their relevance to infertility and reproductive aging.