Regulation of anaphase in mammalian meiosis

Abstract

Missegregation of chromosomes during meiosis leads to formation of aneuploid eggs. Estimates suggest that in humans, about 10-30% of fertilised eggs and one-third of all miscarriages are aneuploid. Accurate chromosome segregation depends on the coordination between stepwise cohesion resolution and attachments of homologous chromosomes through kinetochores to microtubules, emanating from opposite poles of the cell. The Spindle Assembly Checkpoint (SAC) monitors microtubule-kinetochore attachments and prevents resolution of cohesin complexes by inhibiting the ubiquitin ligase APC/CCdc20 until all aberrant microtubule-kinetochore attachments have been rectified by an Aurora Kinase-dependent error correction machinery. During meiosis, these pathways work in seamless coordination to achieve balanced segregation of the genome at the first meiotic division.The cross-talk between different cell cycle pathways requires members with shared affiliations. During my DPhil studies, I worked on understanding the role of two such proteins, namely Bub1 (budding uninhibited by benzimidazoles 1) and Sgol2 (Shugoshin-like protein 2) in mouse oocytes.During the first meiotic division, Bub1 maintains the SAC, and through its kinase activity, Bub1 recruits Sgol2 to kinetochores to protect centromeric cohesion. This recruitment is essential for two rounds of chromosomes segregation in meiosis. Thus, Bub1 localisation at kinetochores can coordinate the timing of anaphase with the centromeric cohesion protection.During the first meiotic division, Sgol2 protects centromeric cohesion by recruiting PP2A to kinetochores, accelerates cohesin resolution by silencing the SAC through its interaction with PP2A and Mad2, and also promotes biorientation and congression of homologous chromosomes by its interaction with MCAK and through dephosphorylation of Aurora B/C kinase substrates at kinetochores.This research revealed that Bub1 and Sgol2 can regulate anaphase by linking multiple cell cycle pathways that work together to achieve faithful chromosomes segregation in mammalian meiosis.This thesis is not currently available via ORA