Abstract
Orderly chromosome segregation during the first meiotic division requires meiotic recombination to form crossovers between homologous chromosomes (homologues). Members of the minichromosome maintenance (MCM) helicase family have been implicated in meiotic recombination. In addition, they have roles in initiation of DNA replication, DNA mismatch repair and mitotic DNA double-strand break repair. Here, we addressed the function of MCMDC2, an atypical yet conserved MCM protein, whose function in vertebrates has not been reported. While we did not find an important role for MCMDC2 in mitotically dividing cells, our work revealed that MCMDC2 is essential for fertility in both sexes due to a crucial function in meiotic recombination. Meiotic recombination begins with the introduction of DNA double-strand breaks into the genome. DNA ends at break sites are resected. The resultant 3-prime single-stranded DNA overhangs recruit RAD51 and DMC1 recombinases that promote the invasion of homologous duplex DNAs by the resected DNA ends. Multiple strand invasions on each chromosome promote the alignment of homologous chromosomes, which is a prerequisite for inter-homologue crossover formation during meiosis. We found that although DNA ends at break sites were evidently resected, and they recruited RAD51 and DMC1 recombinases, these recombinases were ineffective in promoting alignment of homologous chromosomes in the absence of MCMDC2. Consequently, RAD51 and DMC1 foci, which are thought to mark early recombination intermediates, were abnormally persistent in Mcmdc2-/- meiocytes. Importantly, the strand invasion stabilizing MSH4 protein, which marks more advanced recombination intermediates, did not efficiently form foci in Mcmdc2-/- meiocytes. Thus, our work suggests that MCMDC2 plays an important role in either the formation, or the stabilization, of DNA strand invasion events that promote homologue alignment and provide the basis for inter-homologue crossover formation during meiotic recombination.
Highlights
Chromosome segregation during the first meiotic division uniquely differs from chromosome segregation during mitosis and the second meiotic division [1,2]
We discovered that meiotic recombination critically depends on the helicase-related minichromosome maintenance domain containing 2 protein (MCMDC2)
This work reveals a crucial role for MCMDC2 in recombination in mammals, and constitutes an important step in understanding how recombination establishes connections between homologous chromosomes during meiosis
Summary
Chromosome segregation during the first meiotic division uniquely differs from chromosome segregation during mitosis and the second meiotic division [1,2]. Centromeres belonging to homologous chromosomes (homologues) that originate from different parents are pulled to opposite spindle poles during the first meiotic division This bi-orientation of homologue centromeres requires homologues to pair and become physically linked before segregation [1,2]. Meiotic recombination initiates with the programmed generation of large numbers of DNA double-strand breaks (DSBs) (200–400 per cell in mice and humans) by the SPO11 enzyme [3,4,5,6,7] This results in SPO11-bound DNA ends at break sites [3,4], which are processed to remove SPO11 from DNA –ends and to produce singlestranded 3 ́ DNA overhangs [8]. This inter-homologue bias in the formation of recombination intermediates is thought to ensure that DSBs efficiently promote the recognition and the pairing of homologues based on sequence similarity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
