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

DOI: 10.1038/s41467-020-15954-x DOI Help

Authors: Jingjing Zhang (University of Gothenburg) , Manickam Gurusaran (Newcastle University) , Yasuhiro Fujiwara (University of Tokyo) , Kexin Zhang (University of Gothenburg) , Meriem Echbarthi (University of Gothenburg) , Egor Vorontsov (University of Gothenburg) , Rui Guo (University of Pennsylvania School of Veterinary Medicine) , Devon F. Pendlebury (University of Michigan) , Intekhab Alam (Case Western Reserve University; University of Michigan) , Gabriel Livera (Université de Paris, Université Paris Saclay, CEA) , Martini Emmanuelle (Université de Paris, Université Paris Saclay, CEA) , P. Jeremy Wang (University of Pennsylvania School of Veterinary Medicine) , Jayakrishnan Nandakumar (University of Michigan) , Owen Davies (Newcastle University) , Hiroki Shibuya (University of Gothenburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: April 2020

Open Access Open Access

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.

Journal Keywords: Chromosomes; Meiosis

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: B21-High Throughput SAXS