title: MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination.
abstract: We generated knockout mice for MCM8 and MCM9 and show that deficiency for these genes impairs homologous recombination (HR)-mediated DNA repair during gametogenesis and somatic cells cycles. MCM8(-/-) mice are sterile because spermatocytes are blocked in meiotic prophase I, and females have only arrested primary follicles and frequently develop ovarian tumors. MCM9(-/-) females also are sterile as ovaries are completely devoid of oocytes. In contrast, MCM9(-/-) testes produce spermatozoa, albeit in much reduced quantity. Mcm8(-/-) and Mcm9(-/-) embryonic fibroblasts show growth defects and chromosomal damage and cannot overcome a transient inhibition of replication fork progression. In these cells, chromatin recruitment of HR factors like Rad51 and RPA is impaired and HR strongly reduced. We further demonstrate that MCM8 and MCM9 form a complex and that they coregulate their stability. Our work uncovers essential functions of MCM8 and MCM9 in HR-mediated DSB repair during gametogenesis, replication fork maintenance, and DNA repair.
authors: DNA Replication and Genome Dynamics, Institute of Human Genetics, CNRS, 141 Rue de la Cardonille, 34396 Montpellier, Cedex 5, France.
authors: Malik
authors: M
authors: Lutzmann
authors: Corinne
authors: C
authors: Grey
authors: Sabine
authors: S
authors: Traver
authors: Olivier
authors: O
authors: Ganier
authors: Apolinar
authors: A
authors: Maya-Mendoza
authors: Noemie
authors: N
authors: Ranisavljevic
authors: Florence
authors: F
authors: Bernex
authors: Atsuya
authors: A
authors: Nishiyama
authors: Nathalie
authors: N
authors: Montel
authors: Elodie
authors: E
authors: Gavois
authors: Luc
authors: L
authors: Forichon
authors: Bernard
authors: B
authors: de Massy
authors: Marcel
authors: M
authors: Méchali
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D004260:DNA Repair; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005718:Gametogenesis / Q000235:genetics*; D042822:Genomic Instability; D005854:Germ Cells / Q000378:metabolism; D059765:Homologous Recombination / Q000235:genetics*; D008297:Male; D049469:Meiotic Prophase I / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D064110:Minichromosome Maintenance Proteins; D010053:Ovary / Q000378:metabolism; D013090:Spermatocytes / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C501932:Mcm9 protein, mouse; D064110:Minichromosome Maintenance Proteins