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

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 and Hiroki Shibuya ()
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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: 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 R. Davies: Newcastle University
Hiroki Shibuya: University of Gothenburg

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15954-x

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