Meiotic chromosome segregation is essential for gamete formation in all sexually reproducing organisms, including humans. Prior to segregation, homologous chromosomes (homologs) undergo pairing and recombination giving rise to crossovers. Crossovers provide physical connections that mediate bipolar homolog segregation. Without crossovers, gametes with unbalanced chromosome content form, a condition associated with birth defects and sterility. Crossovers are formed by induction of double strand breaks (DSBs) at multiple chromosome positions. The principal investigator?s long term goal is to understand the functional integration of meiotic chromosome structure, and recombination. The current proposal aims to identify the role of the 26S proteasome along meiotic chromosomes. We have recently discovered that the 26S proteasome is recruited in an evolutionarily conserved manner to meiotic chromosomes where it is required for pairing of homologous chromosomes and recombination. The proteasome is the main site of protein degradation in all eukaryotes. It is a multicomponent, compartmentalized protease that resides both in the cytoplasm and the nucleus. While cytoplasmic proteasome functions in eliminating misfolded and short-lived, regulatory proteins have been recognized for a long time, functions of the proteasome in the nucleus are much less understood. Using a combination of microscopy, genetic and proteomic approaches, we will pursue the following aims: First, we will use tightly controlled conditional alleles to systematically characterize the contribution of the proteasome to distinct meiotic functions. Second, we will identify degradation substrates of the proteasome relevant for chromosome pairing and recombination, thereby providing insights into a novel class of molecules that coordinate the meiotic program by preventing precocious progression of a subset of chromosomal events. Meiotic chromosome segregation defects in absence of a functional proteasome emphasize the importance of an improved understanding of this process. We will determine the overall composition of the proteasome and factors that control its localization to distinct positions along meiotic chromosomes. These studies provide a unique opportunity to determine to what extent proteolytic core and potentially alternative regulatory proteasome particles cooperate along meiotic chromosomes. This analysis of proteasome functions in recombination and homolog pairing will pave the way towards a better understanding how chromosome- associated proteolysis is used in living cells, and how interference with proteasome function, e.g. in cancer therapy, can impact fertility and reproductive health.
Up to 30% of clinically recognized human pregnancies exhibit aneuploidies, i.e. a deficit or surplus of one or several chromosomes. Chromosome missegregation during meiosis contributes to most such imbalances, making meiotic mistakes the leading cause of birth defects and infertility in humans. A mechanistic understanding of meiotic chromosome segregation is essential to make this problem accessible to future medical intervention.
