Robust designation of meiotic crossover sites by CDK-2 through phosphorylation of the MutSγ complex

Abstract

Significance Successful chromosome segregation during meiosis relies on crossover recombination between homologous chromosomes. Meiotic recombination initiates with the formation of numerous DNA double-strand breaks, but only a few are ultimately selected to become crossovers. How this process is regulated to ensure that each homolog pair designates at least one crossover remains poorly understood. Here, we show that the Caenorhabditis elegans kinase CDK-2 partners with cyclin-like protein COSA-1 and promotes crossover designation through phosphorylation and activation of the MutSγ complex. Our data support a model in which scaffold-like properties of the MSH-5 C-terminal tail and its CDK-2–mediated phosphorylation combine to promote full recruitment and activity of crossover–promoting complexes, thereby generating positive feedback that contributes to the robustness of crossover designation.

Joint control of meiotic crossover patterning by the synaptonemal complex and HEI10 dosage

“…A similar model was proposed and further supporting experimental data were recently obtained in C. elegans 17 , 36 . Several additional pieces of evidence suggest that the joint control of COs by SC and HEI10 is conserved: In multiple species, HEI10 homologs also initially form multiple foci before eventually consolidating into a limited number of large foci that co-localize with COs 19 – 22 , 37 ; COs covary with SC length in many species 13 ; Variants that affect recombination rates in natural populations of diverse species involve genes that encode HEI10 homologs 38 .…”

Cyclins and CDKs in the regulation of meiosis-specific events

“…Absence of bivalents in CDK-2 depleted oocytes reflects a failure to properly generate COs. Specifically, the CO selection pathway is disrupted, as seen by the fact that ZHP-3 (RNF212 in mouse) and MSH-5 (component of the conserved MutSγ complex) signals fail to restrict to the six CO sites as normally happens in late pachytene ( Haversat et al, 2022 ). Some studies identified the cyclin-like protein COSA-1 ( C r o ssover S ite- A ssociated-1) as a partner for CDK-2 in C. elegans meiosis.…”

“…In the cosa-1 mutant, bivalents are also absent, and at late pachytene ZHP-3 aberrantly remains at high levels along the SC and MSH5 foci are lost ( Yokoo et al, 2012 ). Moreover, in vitro experiments showed that CDK-2 and COSA-1 are able to form a complex ( Haversat et al, 2022 ).…”

“…Key meiotic substrates of CDK2 for this crossover-related function are not clearly determined. Recent studies describe MSH-5 as a key target in C. elegans ( Haversat et al, 2022 ). MSH-5 contains thirteen CDK consensus motifs in a disordered C-terminal tail, and this domain is essential for its function in CO formation.…”

“…Moreover, at late prophase colocalization between MSH-5 13A and COSA-1 is lost and the MSH-5 13A protein persists as multiple foci instead of pairing down to six bright foci, reminiscent of what it is observed in CDK-2 depleted germlines. The disordered C-terminal tail containing CDK sites in MSH-5 is not conserved outside Caenorhabditis species, indicating that, although the role of CDK2 in CO selection is conserved, the mechanism may differ from one organism to another ( Haversat et al, 2022 ).…”