A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination

Abstract

Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) to maintain genomic integrity. Recombinase recruited to the DSBs by the mediator protein BRCA2 catalyzes the homology-directed repair. During meiotic HR, programmed DSBs are introduced genome-wide but their repair mechanisms, including the regulation of BRCA2, have remained largely elusive. Here we identify a meiotic localizer of BRCA2, MEILB2/HSF2BP, that localizes to the site of meiotic DSBs in mice. Disruption of Meilb2 abolishes the localization of RAD51 and DMC1 recombinases in spermatocytes, leading to errors in DSB repair and male sterility. MEILB2 directly binds to BRCA2 and regulates its association to meiotic DSBs. We map the MEILB2-binding domain within BRCA2 that is distinct from the canonical DNA-binding domain but is sufficient to localize to meiotic DSBs in a MEILB2-dependent manner. We conclude that localization of BRCA2 to meiotic DSBs is mediated by MEILB2, which is an integral mechanism to repair abundant meiotic DSBs.

A missense in HSF2BP causing Primary Ovarian Insufficiency affects meiotic recombination by its novel interactor C19ORF57/MIDAP

“…Hsf2bp S167L/S167L male and female mice were able to reproduce but females showed a significant reduction in the number and size of litters ( Figure 1a) whilst males only showed a slight non-significant reduction in fertility ( Figure 1a). This is in agreement with the fertility defects observed in Hsf2bp -/mice (Figure 1c, e-f and (Brandsma et al, 2019;Zhang et al, 2019)), and suggests that the S167L variant might impact more specifically female fertility.…”

“…During the course of this work and in agreement with our results, two independent groups showed that HSF2BP is essential for meiotic recombination through its ability to interact with BRCA2 (Brandsma et al, 2019;Zhang et al, 2019). Here, we report that the introduction of the missense variant HSF2BP-S167L in the mouse leads to subfertility and DNA repair defects during prophase I.…”

A meiosis-specific factor C19orf57/4930432K21Rik/BRME1 modulates localization of RAD51 and DMC1 recombinases to DSBs in mouse meiotic recombination

“…Given that MRM is required for DSB repair, we sought how MRM was involved in DSB repair processes by screening its interacting factors. Mass spectrometry (MS) analysis of immunoprecipitates of MRM from testes extracts identified MEILB2/HSF2BP (Brandsma et al, 2019;Yoshima et al, 1998;Zhang et al, 2019), BRCA2 (Sharan et al, 2004), RPA1 (Wold et al, 1998) and MEIOB (Luo et al, 2013;Souquet et al, 2013), which are known to play a role in meiotic recombination (Fig.3A, B). This suggests that MRM mediates the process of meiotic recombination through the interaction with these factors.…”

“…In plants and mammals, BRCA2 directly interacts with RAD51 and DMC1, and plays an essential role in loading them onto ssDNA-ends (Jensen et al, 2010) (Sharan et al, 2004) (Siaud et al, 2004). Furthermore, recruitment of RAD51 and DMC1 on ssDNA is mediated by MEILB2/HSF2BP through the interaction with BRCA2 (Brandsma et al, 2019;Zhang et al, 2019). Although it has been proposed that MEILB2/HSF2BP-BRCA2 interaction plays a crucial role in the recruitment of RAD51 and DMC1 onto ssDNA, the exact mechanisms how the MEILB2/HSF2BP-BRCA2 complex acts for ssDNA processing remains elusive (Zhang et al, 2019).…”

A homozygous hypomorphic BRCA2 variant causes primary ovarian insufficiency without cancer or Fanconi anemia traits

“…(involving HR) are required to produce functional gametes (Zhang et al, 2019). By contrast, 334 somatic DSBs are introduced by accident and such cells are rarely spontaneously confronted to 335 such high levels of simultaneous DSBs.…”