Abstract

Meiosis is the conduit of heredity, producing haploid gametes containing mosaics of their precursor genomes. Gamete quality control involves regulatory processes that mediate successful execution of a variety of chromosomal processes including pairing and synapsis, homologous recombination, and spindle alignment. Despite these regulatory processes, errors in meiotic chromosome segregation are alarmingly common in humans, especially in females. The ensuing aneuploid gametes are responsible for a large fraction of the estimated 1 million pregnancy miscarriages that occur in the U.S. each year. One focus of our research is to understand how the unique events of meiotic prophase are regulated by post-translational protein modification. Our current emphasis is the regulation of protein dynamics by SUMO , ubiquitin and phosphorylation. At a local level, these modifications are differentially applied and integrated to control the outcome of homologous recombination and ensure that all chromosome pairs undergo crossing over, as required for accurate chromosome segregation at the first meiotic division. More globally, we find that ubiquitylation generally accelerates the turnover of chromosome-associated recombination factors, to promote the progression of recombination and its coordination with chromosome synapsis. Finally, at the cellular level, we have discovered that SUM Oylation plays an essential role to promote apoptosis of oocytes that have experienced defects in chromosome synapsis and/or recombination. As such, SUM Oylation plays a central role in oocyte quality control and determination of ovarian reserve. My talk will be focused around an interdependent pair of RING -domain E3 ligases, RNF212 and HEI10 (a.k.a. CCNBIP1 ); and the MutSγ complex (Msh4-Msh5), a meiosis-specific recombination factor. Intriguingly, alleles of all three factors are associated with heritable variation in recombination rate in humans.