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

Journal article
Authors Jingjing Zhang
Manickam Gurusaran
Yasuhiro Fujiwara
Kexin Zhang
Meriem Echbarthi
Egor Vorontsov
Rui Guo
Devon F Pendlebury
Intekhab Alam
Gabriel Livera
Martini Emmanuelle
P Jeremy Wang
Jayakrishnan Nandakumar
Owen R Davies
Hiroki Shibuya
Published in Nature communications
Volume 11
Issue 1
ISSN 2041-1723
Publication year 2020
Published at Core Facilities, Proteomics
Department of Chemistry and Molecular Biology
Language en
Links dx.doi.org/10.1038/s41467-020-15954...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Biochemistry and Molecular Biology, Cell Biology, Biological Sciences

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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