UC Berkeley

For most eukaryotes, recombination between homologous chromosomes during meiosis is an essential aspect of sexual reproduction. Meiotic recombination is initiated by programmed double-strand breaks (DSBs) in the DNA, which have the potential to induce mutations if not efficiently repaired. The focus of the work presented here is to better understand the mechanisms that govern the initiation of recombination and regulate the formation of DSBs. The nematode Caenorhabditis elegans was used as a model system for these studies. Here I describe the identification of a novel gene, dsb-1, that is required for DSB formation in C. elegans. Through analysis of DSB-1 I illuminate two important regulatory pathways that control the initiation of meiotic recombination and regulate DSB number.

The first regulatory pathway presented in this work is the crossover assurance checkpoint, which promotes crossover recombination events on all chromosome pairs to ensure successful meiosis. Under the crossover assurance checkpoint, DSB formation is prolonged when one or more homologous chromosome pair fails to form a crossover precursor. This increase in meiotic recombination initiation events gives cells additional opportunities to produce the crossovers necessary for proper chromosome segregation.

I also present evidence for a separate regulatory pathway that functions to limit the number of DSBs. I describe a negative feedback loop that is mediated by DNA-damage response kinases ATM and ATR and acts though DSB-1 to down-regulate DSB formation. This regulatory pathway permits the formation of a limited number of meiotic DSBs, while preventing excess DSB levels. Furthermore, my results demonstrate the resilience of meiotic cells in tolerating excess levels of meiotic DSBs without negative consequences for genomic integrity or crossover regulation.

The work presented here provides important insights into the regulation of meiotic recombination initiation. Although the regulatory pathways described here were identified in C. elegans, recent studies suggest that similar regulatory pathways are likely to be conserved in other organisms. Therefore this work is important not only for understanding DSB regulation in C. elegans, but may also shed light on the regulation of meiotic DSBs in other eukaryotic organisms.