BRIT1 protein (also known as MCPH1) contains 3 BRCT domains which are conserved in BRCA1, BRCA2, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. BRIT1 mutations or aberrant expression are found in primary microcephaly patients as well as in cancer patients. Recent in vitro studies suggest that BRIT1/MCPH1 functions as a novel key regulator in the DNA damage response pathways. To investigate its physiological role and dissect the underlying mechanisms, we generated BRIT1(-/-) mice and identified its essential roles in mitotic and meiotic recombination DNA repair and in maintaining genomic stability. Both BRIT1(-/-) mice and mouse embryonic fibroblasts (MEFs) were hypersensitive to gamma-irradiation. BRIT1(-/-) MEFs and T lymphocytes exhibited severe chromatid breaks and reduced RAD51 foci formation after irradiation. Notably, BRIT1(-/-) mice were infertile and meiotic homologous recombination was impaired. BRIT1-deficient spermatocytes exhibited a failure of chromosomal synapsis, and meiosis was arrested at late zygotene of prophase I accompanied by apoptosis. In mutant spermatocytes, DNA double-strand breaks (DSBs) were formed, but localization of RAD51 or BRCA2 to meiotic chromosomes was severely impaired. In addition, we found that BRIT1 could bind to RAD51/BRCA2 complexes and that, in the absence of BRIT1, recruitment of RAD51 and BRCA2 to chromatin was reduced while their protein levels were not altered, indicating that BRIT1 is involved in mediating recruitment of RAD51/BRCA2 to the damage site. Collectively, our BRIT1-null mouse model demonstrates that BRIT1 is essential for maintaining genomic stability in vivo to protect the hosts from both programmed and irradiation-induced DNA damages, and its depletion causes a failure in both mitotic and meiotic recombination DNA repair via impairing RAD51/BRCA2's function and as a result leads to infertility and genomic instability in mice.
Pubmed ID: 20107607 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Susan G. Komen for the Cure is the global leader of the breast cancer movement, having invested more than $1.9 billion since inception in 1982. As the world''s largest grassroots network of breast cancer survivors and activists, we''re working together to save lives, empower people, ensure quality care for all and energize science to find the cures. Thanks to events like the Susan G. Komen Race for the Cure and the Susan G. Komen 3-Day for the Cure, and generous contributions from our partners, sponsors and fellow supporters, we have become the largest source of nonprofit funds dedicated to the fight against breast cancer in the world.
View all literature mentionsFederal government agency for cancer research and training established in 1937. National Cancer Program is responsibility of NCI to coordinate, conduct and support research, training, health information dissemination with respect to cause, diagnosis, prevention, and treatment of cancer, rehabilitation from cancer, and continuing care of cancer patients and families of cancer patients. Supports construction of laboratories, clinics, and related facilities necessary for cancer research through award of grants.
View all literature mentionsFederal government agency for cancer research and training established in 1937. National Cancer Program is responsibility of NCI to coordinate, conduct and support research, training, health information dissemination with respect to cause, diagnosis, prevention, and treatment of cancer, rehabilitation from cancer, and continuing care of cancer patients and families of cancer patients. Supports construction of laboratories, clinics, and related facilities necessary for cancer research through award of grants.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentions