Genetic Evidence That Synaptonemal Complex Axial Elements Govern Recombination Pathway Choice in Mice

Abstract

Abstract Chiasmata resulting from interhomolog recombination are critical for proper chromosome segregation at meiotic metaphase I, thus preventing aneuploidy and consequent deleterious effects. Recombination in meiosis is driven by programmed induction of double strand breaks (DSBs), and the repair of these breaks occurs primarily by recombination between homologous chromosomes, not sister chromatids. Almost nothing is known about the basis for recombination partner choice in mammals. We addressed this problem using a genetic approach. Since meiotic recombination is coupled with synaptonemal complex (SC) morphogenesis, we explored the role of axial elements – precursors to the lateral element in the mature SC - in recombination partner choice, DSB repair pathways, and checkpoint control. Female mice lacking the SC axial element protein SYCP3 produce viable, but often aneuploid, oocytes. We describe genetic studies indicating that while DSB-containing Sycp3−/− oocytes can be eliminated efficiently, those that survive have completed repair before the execution of an intact DNA damage checkpoint. We find that the requirement for DMC1 and TRIP13, proteins normally essential for recombination repair of meiotic DSBs, is substantially bypassed in Sycp3 and Sycp2 mutants. This bypass requires RAD54, a functionally conserved protein that promotes intersister recombination in yeast meiosis and mammalian mitotic cells. Immunocytological and genetic studies indicated that the bypass in Sycp3−/− Dmc1−/− oocytes was linked to increased DSB repair. These experiments lead us to hypothesize that axial elements mediate the activities of recombination proteins to favor interhomolog, rather than intersister recombinational repair of genetically programmed DSBs in mice. The elimination of this activity in SYCP3- or SYCP2-deficient oocytes may underlie the aneuploidy in derivative mouse embryos and spontaneous abortions in women.