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The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells

Lookup NU author(s): Dr Owen Davies

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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.

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Author(s): Zhang J, Gurusaran M, Fujiwara Y, Zhang K, Echbarthi M, Vorontsov E, Guo R, Pendlebury DF, Alam I, Livera G, Emmanuelle M, Wang PJ, Nandakumar J, Davies OR, Shibuya H

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2020

Volume: 11

Online publication date: 28/04/2020

Acceptance date: 03/04/2020

Date deposited: 02/08/2021

ISSN (electronic): 2041-1723

Publisher: Nature Research

URL: https://doi.org/10.1038/s41467-020-15954-x

DOI: 10.1038/s41467-020-15954-x

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