Abstract
Breast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR). In meiosis, BRCA2 binds to MEILB2 to localize to DNA double-strand breaks (DSBs). Here, we identify BRCA2 and MEILB2-associating protein 1 (BRME1), which functions as a stabilizer of MEILB2 by binding to an α-helical N-terminus of MEILB2 and preventing MEILB2 self-association. BRCA2 binds to the C-terminus of MEILB2, resulting in the formation of the BRCA2-MEILB2-BRME1 ternary complex. In Brme1 knockout (Brme1−/−) mice, the BRCA2-MEILB2 complex is destabilized, leading to defects in DSB repair, homolog synapsis, and crossover formation. Persistent DSBs in Brme1−/− reactivate the somatic-like DNA-damage response, which repairs DSBs but cannot complement the crossover formation defects. Further, MEILB2-BRME1 is activated in many human cancers, and somatically expressed MEILB2-BRME1 impairs mitotic HR. Thus, the meiotic BRCA2 complex is central in meiotic HR, and its misregulation is implicated in cancer development.
Highlights
Breast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR)
We find that Breast cancer susceptibility gene 2 (BRCA2)-MEILB2-BRCA2 and MEILB2-associating protein 1 (BRME1) forms a stable ternary complex specific to meiosis, and in vivo genetic analyses clarify the mechanism that governs the assembly of BRCA2-MEILB2BRME1 on meiotic ssDNA and the essential function of BRCA2MEILB2-BRME1 in meiotic double-strand breaks (DSBs) repair, homologous synapsis, and crossover formation
Consistent with the notion that DSB repair and subsequent homologous synapsis are a prerequisite for crossover formation, we found a significant reduction in foci number of the type I crossover marker MutL homolog 1 (MLH1)[20] in Brme1−/− spermatocytes compared with WT (Fig. 7a)
Summary
Breast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR). In Brme[1] knockout (Brme1−/−) mice, the BRCA2MEILB2 complex is destabilized, leading to defects in DSB repair, homolog synapsis, and crossover formation. The primary function of mitotic BRCA2 is thought to be the loading of recombinase RAD51 onto DNA double-strand breaks (DSBs), which promotes their homology-directed repair[4,5]. The identification of MEILB2 shed light on the integral roles of BRCA2-MEILB2 in meiotic HR, how BRCA2 switches its roles from mitotic to meiotic HR and mediates meiosis-specific events, such as homologous synapsis and crossover formation, has been largely unclear. We find that BRCA2-MEILB2-BRME1 forms a stable ternary complex specific to meiosis, and in vivo genetic analyses clarify the mechanism that governs the assembly of BRCA2-MEILB2BRME1 on meiotic ssDNA and the essential function of BRCA2MEILB2-BRME1 in meiotic DSB repair, homologous synapsis, and crossover formation. We demonstrate that MEILB2BRME1 is a potential proto-oncogene that impairs mitotic BRCA2 functions, in sharp contrast to its meiotic roles
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