Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Finsterbusch, Friederike, Ravindranathan, Ramya, Dereli, Ihsan, Stanzione, Marcello, Tränkner, Daniel, Tóth, Attila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070785/
https://www.ncbi.nlm.nih.gov/pubmed/27760146
http://dx.doi.org/10.1371/journal.pgen.1006393
_version_ 1782461197302366208
author Finsterbusch, Friederike
Ravindranathan, Ramya
Dereli, Ihsan
Stanzione, Marcello
Tränkner, Daniel
Tóth, Attila
author_facet Finsterbusch, Friederike
Ravindranathan, Ramya
Dereli, Ihsan
Stanzione, Marcello
Tränkner, Daniel
Tóth, Attila
author_sort Finsterbusch, Friederike
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5070785
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-50707852016-10-27 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 Finsterbusch, Friederike Ravindranathan, Ramya Dereli, Ihsan Stanzione, Marcello Tränkner, Daniel Tóth, Attila PLoS Genet Research Article 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. Public Library of Science 2016-10-19 /pmc/articles/PMC5070785/ /pubmed/27760146 http://dx.doi.org/10.1371/journal.pgen.1006393 Text en © 2016 Finsterbusch et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Finsterbusch, Friederike
Ravindranathan, Ramya
Dereli, Ihsan
Stanzione, Marcello
Tränkner, Daniel
Tóth, Attila
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070785/
https://www.ncbi.nlm.nih.gov/pubmed/27760146
http://dx.doi.org/10.1371/journal.pgen.1006393
work_keys_str_mv AT finsterbuschfriederike alignmentofhomologouschromosomesandeffectiverepairofprogrammeddnadoublestrandbreaksduringmousemeiosisrequiretheminichromosomemaintenancedomaincontaining2mcmdc2protein
AT ravindranathanramya alignmentofhomologouschromosomesandeffectiverepairofprogrammeddnadoublestrandbreaksduringmousemeiosisrequiretheminichromosomemaintenancedomaincontaining2mcmdc2protein
AT dereliihsan alignmentofhomologouschromosomesandeffectiverepairofprogrammeddnadoublestrandbreaksduringmousemeiosisrequiretheminichromosomemaintenancedomaincontaining2mcmdc2protein
AT stanzionemarcello alignmentofhomologouschromosomesandeffectiverepairofprogrammeddnadoublestrandbreaksduringmousemeiosisrequiretheminichromosomemaintenancedomaincontaining2mcmdc2protein
AT tranknerdaniel alignmentofhomologouschromosomesandeffectiverepairofprogrammeddnadoublestrandbreaksduringmousemeiosisrequiretheminichromosomemaintenancedomaincontaining2mcmdc2protein
AT tothattila alignmentofhomologouschromosomesandeffectiverepairofprogrammeddnadoublestrandbreaksduringmousemeiosisrequiretheminichromosomemaintenancedomaincontaining2mcmdc2protein