Abstract
Orderly chromosome segregation is enabled by crossovers between homologous chromosomes in the first meiotic division. Crossovers arise from recombination-mediated repair of programmed DNA double-strand breaks (DSBs). Multiple DSBs initiate recombination, and most are repaired without crossover formation, although one or more generate crossovers on each chromosome. Although the underlying mechanisms are ill-defined, the differentiation and maturation of crossover-specific recombination intermediates requires the cyclin-like CNTD1. Here, we identify PRR19 as a partner of CNTD1. We find that, like CNTD1, PRR19 is required for timely DSB repair and the formation of crossover-specific recombination complexes. PRR19 and CNTD1 co-localise at crossover sites, physically interact, and are interdependent for accumulation, indicating a PRR19-CNTD1 partnership in crossing over. Further, we show that CNTD1 interacts with a cyclin-dependent kinase, CDK2, which also accumulates in crossover-specific recombination complexes. Thus, the PRR19-CNTD1 complex may enable crossover differentiation by regulating CDK2.
Highlights
Chromosome segregation is enabled by crossovers between homologous chromosomes in the first meiotic division
Similar PRR19 staining was observed in foetal oocytes at 18 days post coitum, where most oocytes were in the mid/late pachytene (Supplementary Fig. 1e)
PRR19 localisation resembled the localisation of crossover-specific recombination complexes, and PRR19 co-localised with the crossover marker MLH1 in spermatocytes (Fig. 1d, e)
Summary
Chromosome segregation is enabled by crossovers between homologous chromosomes in the first meiotic division. Like CNTD1, PRR19 is required for timely DSB repair and the formation of crossover-specific recombination complexes. Meiocytes form many more DSBs (~200–400 in mice) than crossovers (~20–30, or one-to-two per homolog pair), most DNA-strand-invasion intermediates are resolved without crossover formation (called non-crossovers)[1]. Most crossovers (90–95%) are generated by the class I pathway, which relies on the putative crossover-resolvase MutLγ complex (MLH1/MLH3)[3,4,5,6,7,8,9] This pathway is subject to poorly understood regulatory mechanisms that differentiate at least one recombination intermediate into crossover on each chromosome (crossover assurance), and prevent the formation of crossovers in close proximity to one another Beyond RNF212 and MutSγ, the HEI10 ubiquitin ligase[15] and the cyclin-like CNTD116 are crucial for crossover differentiation and the underlying reduction in the number of stabilised recombination complexes in mid pachytene. Whereas it is unknown how CNTD1 functions, HEI1015,17 is inferred to destabilise recombination intermediates by ubiquitinating recombination proteins and targeting them for degradation by chromosome axis-bound 26S proteasomes[15,18,19]
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