Wednesday, March 12, 2025
3/12/2025
PROJECT SUMMARY Failure to achieve accurate chromosome segregation during meiosis is a leading cause of miscarriages, infertility, and birth defects such as Down syndrome. Therefore, understanding the mechanisms underlying accurate meiotic chromosome segregation is of paramount importance to human health. The synaptonemal complex (SC) is a zipper-like structure present from yeast to humans during meiosis that assembles between homologous chromosomes, stabilizing homologous pairing interactions and promoting interhomolog crossover formation. However, despite its importance for achieving accurate meiotic chromosome segregation, the mechanisms regulating chromosome synapsis and how the SC interfaces with recombination and chromosome remodeling is not well understood in any organism. Our goal is to identify mechanisms regulating the SC and to determine how SC regulation is linked to DNA double-strand break (DSB) repair progression and late prophase I chromosome remodeling to ensure accurate meiotic chromosome segregation. We study this in the nematode C. elegans because it shares a high degree of gene conservation with humans and affords ease of genetic, cytological, molecular, and biochemical analysis for germline studies. Our progress during the previous funding period, coupled with new data and molecular targets, place us in an ideal position to understand the regulation and roles of chromosome synapsis during meiosis. Here we propose two integrated aims to address these critical issues. Aim 1 will determine how HIM-22, a protein which shares sequence conservation with yeast Set3 and human ASH1L, regulates SC formation. HIM-22 promotes protein deacetylation in the germline, interacts with a structural component of the SC, and is required for regulating SC assembly, crossover levels, and late prophase I chromosome remodeling; this will define a previously unknown meiotic role for this protein modifier in a metazoan and a new mode of SC regulation. Aim 2 will determine how NatF-mediated N-terminal acetylation of meiotic proteins regulates the SC. Our studies show that NatF is required for protein acetylation in the germline, and regulates SC assembly/disassembly, DSB repair progression, crossover distribution, and late prophase I chromosome remodeling. We previously found that NatB-mediated N-terminal acetylation of a structural component of the SC promotes SC assembly. Our past studies on NatB and our current discovery of NatF as a potential regulator of the SC suggest there is a conserved yet poorly understood regulatory network of different N-acetyltransferases acting on chromosome synapsis. These studies will shed new light on our understanding of the mechanisms regulating chromosome synapsis and how these link the SC to DSB repair and late prophase I chromosome remodeling. Our studies will impact multiple fields of tremendous relevance to human health including chromosome dynamics, the study of post-translational modifications, and regulation of macromolecular structures. Taken together, this application will provide novel insights into the molecular mechanisms regulating accurate chromosome segregation during meiosis.
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