My goal is to understand the mechanisms that coordinate higher order chromosome structure with formation and repair of DNA double-stranded breaks (DSBs) during meiosis, the cell division program that produces haploid gametes from diploid germ cells. Control of chromosome structure is crucial in meiosis, where DSBs are intentionally induced and repaired to form chiasmata linking chromosomes in preparation for homolog separation. The C. elegans CHK-2 protein has been identified as a key coordinator of chromosome structure, pairing, and initiation of DSB formation in meiosis. CHK-2 is an ortholog of the mammalian DNA damage checkpoint kinase Chk2, which is mutated in the familial cancer syndrome Li Fraumeni. This proposal outlines my strategy to reveal the network of control by which CHK-2 coordinates meiotic chromosome organization and DNA metabolic events to ensure genomic integrity. I will identify CHK-2 binding proteins and phosphorylation targets and determine their meiotic functions. I will test hypotheses about the mechanisms CHK-2 employs in chromosome reorganization, pairing and DSB formation. I will engineer an inactivatable CHK-2 enzyme to investigate possible CHK-2 roles after DSB formation in meiosis. ? ? ?
