Abstract
Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) to maintain genomic integrity. Recombinase recruited to the DSBs by the mediator protein BRCA2 catalyzes the homology-directed repair. During meiotic HR, programmed DSBs are introduced genome-wide but their repair mechanisms, including the regulation of BRCA2, have remained largely elusive. Here we identify a meiotic localizer of BRCA2, MEILB2/HSF2BP, that localizes to the site of meiotic DSBs in mice. Disruption of Meilb2 abolishes the localization of RAD51 and DMC1 recombinases in spermatocytes, leading to errors in DSB repair and male sterility. MEILB2 directly binds to BRCA2 and regulates its association to meiotic DSBs. We map the MEILB2-binding domain within BRCA2 that is distinct from the canonical DNA-binding domain but is sufficient to localize to meiotic DSBs in a MEILB2-dependent manner. We conclude that localization of BRCA2 to meiotic DSBs is mediated by MEILB2, which is an integral mechanism to repair abundant meiotic DSBs.
Highlights
Repaired DNA lesions lead to genomic rearrangements, a hallmark of cancer cells[2]
We show that meiotic localizer of BRCA2 (MEILB2) binds directly to breast cancer susceptibility gene 2 (BRCA2) and is responsible for BRCA2 localization at the meiotic double-strand breaks (DSBs), and this accounts for the impaired recombinase localization observed in Meilb[2] KO mice
One of the candidate genes of unknown function, 4932437G14Rik, known as Heat shock factor 2-binding protein (Hsf2bp), showed a characteristic localization pattern in early prophase I spermatocytes in which punctate signals were formed along the chromosome axes similar to the distribution of meiotic recombination nodules (Fig. 1a)
Summary
Repaired DNA lesions lead to genomic rearrangements, a hallmark of cancer cells[2]. The RAD51 nucleoprotein filament subsequently catalyzes DNA strand exchange between sister chromatids in order to perform homology-directed repair. Mutation of BRCA2 disrupts these HR processes and forces cells to repair the DSBs by more error-prone pathways, which threatens genomic integrity[6]. DMC1 switches the repair template from sister chromatids to homologous chromosomes, creating the so-called homolog bias that is specific to meiosis[22]. These findings suggest that DMC1, with the aid of RAD51, plays a central role in repairing meiotic. The localization of recombinases to the meiotic DSBs is impaired in the presence of Brca[2] mutations. The detailed molecular regulation of the assembly of the recombinase complexes and the role of BRCA2 in meiotic DSBs has remained poorly understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
