Dbf4-dependent kinase promotes meiotic DNA end resection through cyclin-dependent kinase 12 and DNA-2 in Caenorhabditis elegans

Abstract

Meiotic crossovers depend on the accurate processing of programmed DNA double-strand breaks by homologous recombination, which involves generating by resection the single-stranded DNA ends required for the subsequent strand invasion step. How regulatory kinases control DNA end resection in animal meiosis remains poorly understood. Here, we identify the Caenorhabditis elegans Dbf4-dependent kinase (DDK) complex, composed of CDC-7 and DBF-4, and identify CDK-12 as a candidate substrate. DDK promotes efficient meiotic DNA end resection, while crossover formation remains largely preserved in its absence. Loss of DDK function leads to SPO-11-dependent chromosome bridges at diakinesis that arise from recombination intermediates formed early in recombination. In addition to chromosome bridges, we observed elevated heterologous recombination that occurs independently of the canonical or alternative end-joining pathways. Interestingly, CDC-7 and DBF-4 localize dynamically during prophase I and load onto DNA in a hierarchical manner that depends on the BRC-1-BRD-1 complex. Epistasis analysis placed CDC-7 and CDK-12 within the DNA-2-dependent branch of long-range DNA resection. Together, our findings reveal an unidentified DDK/CDK-12/DNA-2 signaling axis that promotes efficient meiotic DNA resection to avoid the generation of aberrant recombination outcomes.