Completion of DNA break repair and crossover formation in mammalian meiosis; the critical functions of a previously uncharacterised meiotic protein, MES19
General Genetics and Functional Genome Biology
Final Report Abstract
In meiosis, two consecutive cell divisions lead to generation of haploid gametes from diploid cells. During the first meiotic division, homologous chromosomes (homologues) originating from the father and mother must segregate. The mechanisms preventing segregation errors require that homologues establish physical linkages via crossovers that form by recombination during the first meiotic prophase. Meiotic recombination initiates with the programmed formation of DNA breaks (appr. 200-400 breaks/cell in mice). Single-stranded DNA ends generated by these breaks invade homologous DNA, which leads to the pairing of homologues. Most DNA breaks are repaired by non-crossover recombination, which generates only local gene-conversions but not crossovers, and only few (typically one or two in mice) breaks are turned into crossovers on each homologue pair. It is essential that at least one crossover forms from the multiple DNA strand-invasion events on each chromosome but it is poorly understood how choices between crossover or non-crossover repair are made, and how distinct recombination pathways are controlled to ensure timely DNA repair. We identified MES19 (hereafter I use the official name, PRR19) in a screen as a meiosisspecific protein that accumulates at crossover sites. Our preliminary data showed that PRR19 is crucial for crossover formation but the precise role of PRR19 was not revealed. Published data showed that the differentiation and maturation of crossover-specific recombination intermediates requires the cyclin-like CNTD1. In the DFG founded project we identified PRR19 as a partner of CNTD1. We found 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, we proposed that PRR19-CNTD1 complex enables differentiation of recombination intermediates as crossovers by regulating CDK2. Additionally, we uncovered a network of direct interactions between PRR19-CNTD1 and other pro-crossover proteins (e.g. MSH4, MLH3, HEI10, and RNF212), placing PRR19-CNTD1 at the centre of meiotic crossover control. Together, our data provide a model (and crucial information for further studies) for the molecular network underlying meiotic crossover formation in mammals, which is highly relevant to the understanding of human reproduction biology and its medical implications.
Publications
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Proline-rich protein PRR19 functions with cyclin-like CNTD1 to promote meiotic crossing over in mouse. Nature Communications, 11(1).
Bondarieva, Anastasiia; Raveendran, Kavya; Telychko, Vladyslav; Rao, H. B. D. Prasada; Ravindranathan, Ramya; Zorzompokou, Chrysoula; Finsterbusch, Friederike; Dereli, Ihsan; Papanikos, Frantzeskos; Tränkner, Daniel; Schleiffer, Alexander; Fei, Ji-Feng; Klimova, Anna; Ito, Masaru; Kulkarni, Dhananjaya S.; Roeder, Ingo; Hunter, Neil & Tóth, Attila
