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

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 selfassociation. 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.

Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States

“…Consistent with that, lack of BRCA2 resulted in impaired recruitment of complexes required for the recombination [31]. Surprisingly, this work also pointed out that Meilb2 mRNA is unusually expressed in some breast cancer cases, and has been recently shown to be directly implicated in cancer [32].…”

A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1

“…As a consequence, zygonema-like spermatocytes accumulate the single strand binding proteins SPATA22 and RPA, whereas oocytes accumulates only SPATA22. During the course of the reviewing of this work, three Brme1 knockouts have been described ( Zhang et al, 2020 ; Shang et al, 2020 ; Takemoto et al, 2020 ). All the described male mutants show strong fertility defects and similar molecular alterations although with different severity.…”

Synaptonemal complex proteins modulate the level of genome integrity in cancers

“…The somatic role of SYCP3 raises a new question: does SYCP3 also inhibit the function of BRCA2 in meiotic recombination in germ cells? In germ cells, BRCA2 binds to the meiosis‐specific proteins MEILB2 and BRME1, resulting in the formation of the stable BRCA2‐MEILB2‐BRME1 ternary complex, which is essential for meiotic DSB repair, homolog synapsis, and cross‐over formation 48 . Interestingly, MEILB2‐BRME1 is ectopically expressed in many human cancers, and somatically expressed MEILB2‐BRME1 impairs mitotic BRCA2 functions, just like somatic SYCP3.…”

“…In addition to studies using mouse genetic models, studies using cultured somatic cells also have the potential to provide novel insights into the link between the SC proteins and the homol- repair, homolog synapsis, and cross-over formation. 48 Interestingly, MEILB2-BRME1 is ectopically expressed in many human cancers, and somatically expressed MEILB2-BRME1 impairs mitotic BRCA2 functions, just like somatic SYCP3. However, the functional interaction between meiotic SYCP3 and meiotic BRCA2 has not been reported yet.…”