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PMID:27760146

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Citation

Finsterbusch, F, Ravindranathan, R, Dereli, I, Stanzione, M, Tränkner, D and Tóth, A (2016) Alignment of Homologous Chromosomes and Effective Repair of Programmed DNA Double-Strand Breaks during Mouse Meiosis Require the Minichromosome Maintenance Domain Containing 2 (MCMDC2) Protein. PLoS Genet. 12:e1006393

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.

Links

PubMed PMC5070785 Online version:10.1371/journal.pgen.1006393

Keywords

Animals; Cell Cycle Proteins/genetics; Chromosome Segregation/genetics; DNA Breaks, Double-Stranded; DNA Repair/genetics; Homologous Recombination/genetics; Male; Meiosis/genetics; Mice; Minichromosome Maintenance Proteins/genetics; Nuclear Proteins/genetics; Oocytes/metabolism; Rad51 Recombinase/genetics; Recombinant Proteins/genetics; Sequence Alignment; Spermatocytes/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MCMD2

acts_upstream_of_or_within

GO:0007283: spermatogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2178050,MGI:MGI:5511194

P

Seeded From UniProt

complete

MOUSE:MCMD2

acts_upstream_of_or_within

GO:0007146: meiotic recombination nodule assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2178050,MGI:MGI:5511194

P

Seeded From UniProt

complete

MOUSE:MCMD2

acts_upstream_of_or_within

GO:0007130: synaptonemal complex assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2178050,MGI:MGI:5511194

P

  • occurs_in:(CL:0000017)|occurs_in:(CL:0000023)

Seeded From UniProt

complete

MOUSE:MCMD2

acts_upstream_of_or_within

GO:0048477: oogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2178050,MGI:MGI:5511194

P

Seeded From UniProt

complete

MOUSE:MCMD2

acts_upstream_of_or_within

GO:0042140: late meiotic recombination nodule assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2178050,MGI:MGI:5511194

P

Seeded From UniProt

complete

MOUSE:MCMD2

acts_upstream_of_or_within

GO:1990918: double-strand break repair involved in meiotic recombination

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2178050,MGI:MGI:5511194

P

Seeded From UniProt

complete

MOUSE:MCMD2

acts_upstream_of_or_within

GO:1990918: double-strand break repair involved in meiotic recombination

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1349669

P

Seeded From UniProt

complete

MOUSE:H2AX

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SYCP3

located_in

GO:0000795: synaptonemal complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RAD51

located_in

GO:0000794: condensed nuclear chromosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:DMC1

located_in

GO:0000794: condensed nuclear chromosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SYCP1

located_in

GO:0000795: synaptonemal complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MSH4

located_in

GO:0005713: recombination nodule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MLH1

located_in

GO:0005715: late recombination nodule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SPO11

acts_upstream_of_or_within

GO:0007130: synaptonemal complex assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2178805

P

Seeded From UniProt

complete

MOUSE:SPO11

acts_upstream_of_or_within

GO:1990918: double-strand break repair involved in meiotic recombination

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:3045334

P

Seeded From UniProt

complete

MOUSE:SYCP1

part_of

GO:0000795: synaptonemal complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:H2AX

part_of

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MLH1

part_of

GO:0005715: late recombination nodule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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