The formation of gametes in most sexually reproducing organisms involves a stage of controlled genome fragmentation and reshuffling known as meiotic recombination. Aside from promoting genetic diversity, the exchange of DNA sequences serves to tether homologous chromosomes, which is essential for controlled chromosome assortment into sperm or eggs. Meiotic recombination is initiated by DNA double strand breaks (DSBs). Because DSBs are inherently difficult to repair, meiotic DSB formation must be tightly regulated to prevent genome rearrangements, aberrant gametes, and birth defects. The overall goal of this project is to define the molecular mechanisms that restrict meiotic DSBs to the appropriate times and genomic locations, and to determine the consequences of inappropriate meiotic DSB formation on DSB repair and genome stability. Meiotic DSB control will be investigated in the sexually reproducing yeast Saccharomyces cerevisiae. Preliminary studies for this project identified two mechanisms of active meiotic DSB suppression: (i) DSB formation is attenuated in response to delayed DNA replication, (ii) DSBs are constitutively suppressed in the vicinity of the highly repetitive ribosomal DNA (rDNA). Those studies furthermore suggested that the coupling between DNA replication and DSB formation is the consequence of a specialized checkpoint mechanism and one component of this checkpoint has been identified. The proposed experiments will use molecular biological, genetic, and genomic approaches to define how this checkpoint regulates the meiotic DSB machinery and to identify additional checkpoint components. Preliminary studies also identified a conserved protein required for the suppression of DSBs in the vicinity of the rDNA and suggested an important role for chromosome structure in this process. The proposed experiments will define the meiotic chromosome structure near the rDNA and determine the effect of this protein on the local activity of the DSB machinery. In addition, genetic assays and physical analysis of repair intermediates will be used to determine the consequences of inappropriate DSB formation on meiotic genome integrity and rDNA repeat stability.
Genome rearrangements and errors in chromosome assortment resulting from inappropriate meiotic recombination are associated with a variety of birth defects, including Down syndrome, Williams syndrome, and Prader-Willi syndrome. By defining the molecular mechanisms that control the initiation of meiotic recombination, this project will provide significant insight into the mechanisms that protect chromosomal integrity during gamete production and will serve as an important framework for the study of birth defects in humans.
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