Control of pairing and recombination during meiosis

Cleveland State University, Cleveland OH

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): Accurate chromosome segregation during meiosis is essential for normal gamete formation in sexually reproducing organisms. Meiotic defects result in reproductive failure and birth defects. Prior to their segregation during meiosis I, homologous chromosomes undergo recombination and close juxtaposition via the synaptonemal complex. Together, these events culminate in the formation of chiasmata/crossovers, physical connections that mediate bipolar attachment of homologs to the meiosis I spindle. Two spatially and temporally integrated pathways contribute to chiasma formation. On the DNA level, homologous sequences undergo pairing, followed by double strand break formation and processing of a non-random subset of double strand breaks into crossovers. At the level of higher order chromosome structure, continuous protein axes form along sister chromatids which become juxtaposed with their homologous partner via the central element of the synaptonemal complex. The function of the synaptonemal complex and the coordination of transitions in chromosome structure and recombination are currently not understood. Our long term goal is to clarify the role in recombination and chromosome segregation of the synaptonemal complex. Our own preliminary findings define early and late recombination functions of the synaptonemal complex component Zip1. A particular Zip1 allele separates functions in recombination from those in SC polymerization. A genome-wide screen has further identified functions in synaptonemal complex formation and recombination of a component of the core proteasome, the machinery that mediates degradation of many proteins. These findings identify proteolysis as an important control mechanism of meiosis. The current proposal aims to dissect early and late functions of the synaptonemal complex by identifying specialized mutant conditions that define SC functions at early and late steps of recombination. As a second aim, the role of proteasome-mediated destruction of regulatory proteins during meiosis will be investigated. Together, our approach will provide a mechanistic understanding of factors with key roles in reproductive health. PUBLIC HEALTH RELEVANCE: Up to 30% of clinically recognized human pregnancies exhibit aneuploidies, i.e. a deficit or surplus of one or several chromosomes. Most chromosomal imbalances result from chromosome missegregation during meiosis. Meiotic mistakes thus are the leading cause of infertility and birth defects in humans. A mechanistic understanding of meiotic mechanisms of chromosome segregation is essential to make this problem accessible to future medical intervention.