Cyclin N-Terminal Domain-Containing-1 Coordinates Meiotic Crossover Formation with Cell-Cycle Progression in a Cyclin-Independent Manner

Abstract

SummaryDuring mammalian meiotic prophase I, programmed DNA double-strand breaks are repaired by non-crossover or crossover events, the latter predominantly occurring via the class I crossover pathway and requiring the cyclin N-terminal domain-containing 1(CNTD1) protein. Using an epitope-tagged Cntd1 allele, we detect a short isoform of CNTD1 in vivo that lacks a predicted N-terminal cyclin domain and does not bind cyclin-dependent kinases. Instead, we find that the short-form CNTD1 variant associates with components of the replication factor C (RFC) machinery to facilitate crossover formation, and with the E2 ubiquitin conjugating enzyme, CDC34, to regulate ubiquitylation and subsequent degradation of the WEE1 kinase, thereby modulating cell-cycle progression. We propose that these interactions facilitate a role for CNTD1 as a stop-go regulator during prophase I, ensuring accurate and complete crossover formation before allowing metaphase progression and the first meiotic division.