MCM8- and MCM9-Deficient Mice Reveal Gametogenesis Defects and Genome Instability Due to Impaired Homologous Recombination

• DOI: 10.1016/j.molcel.2012.05.048
• Publication Date: 2012-07-06T10:39:15Z
• Authors: Malik Lutzmann; Corinne Grey; Sabine Traver; Olivier Ganier; Apolinar Maya-Men...; Noemie Ranisavljevic; Florence Bernex; Atsuya Nishiyama; Nathalie Montel; Elodie Gavois; Luc Forichon; Bernard de Massy; Marcel Méchali
• Keywords: DNA Replication; Male; 0301 basic medicine; 0303 health sciences; DNA Repair; Minichromosome Maintenance Proteins; Ovary; Cell Cycle Proteins; Cell Biology; [SDV.GEN] Life Sciences [q-bio]/Genetics; Fibroblasts; Chromatin; Gametogenesis; Genomic Instability; DNA-Binding Proteins; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Germ Cells; Spermatocytes; Animals; Female; Meiotic Prophase I; Homologous Recombination; Molecular Biology

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.