Impeding DNA Break Repair Enables Oocyte Quality Control

• Published in: Molecular cell 2018-10, Vol.72 (2), p.211-221.e3
• Main Authors: Qiao, Huanyu, Rao, H.B.D. Prasada, Yun, Yan, Sandhu, Sumit, Fong, Jared H., Sapre, Manali, Nguyen, Michael, Tham, Addy, Van, Benjamin W., Chng, Tiffany Y.H., Lee, Amy, Hunter, Neil
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; attrition; Cell Cycle Proteins - genetics; Chromosome Pairing - genetics; DNA Breaks, Double-Stranded; DNA Damage - genetics; DNA Repair - genetics; double strand break; Female; follicle; homologous recombination; HORMAD; Ligases - genetics; Male; meiosis; Meiosis - genetics; Mice; oocyte; Oocytes - physiology; Quality Control; Recombination, Genetic - genetics; RNF212; SUMO
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.08.031

Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death can be triggered by defects in chromosome synapsis and recombination, which involve repair of DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocyte elimination in meiotic mutants require RNF212. RNF212 sensitizes oocytes to DSB-induced apoptosis within a narrow window as chromosomes desynapse and cells transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a “memory” of meiotic defects that enables quality-control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes. [Display omitted] •RNF212, a SUMO ligase required for crossovers, also mediates oocyte quality control•RNF212 promotes apoptosis of oocytes that experienced defects in meiotic prophase I•RNF212 works with HORMAD1 to impede repair of residual DSBs as chromosomes desynapse•Impeded DSBs signal that meiosis was defective and trigger oocyte apoptosis High-quality gametes (sperm and eggs) are paramount for successful reproduction. Defective gametes cause infertility and congenital disorders. Qiao et al. describe a counterintuitive process that helps developing eggs sense whether errors have occurred by impeding the repair of lingering chromosome breaks.