HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required for Mouse Spermatogenesis

Brandsma, Inger; Sato, Koichi; Rossum-Fikkert, Sari E. van; Vliet, Nicole van; Sleddens, Esther; Reuter, Marcel; Odijk, Hanny; Tempel, Nathalie van den; Dekkers, Dick H. W.; Bezstarosti, Karel; Demmers, Jeroen; Maas, Alex; Lebbink, Joyce H.G.; Wyman, Claire; Essers, Jeroen; Gent, Dik C. van; Baarends, Willy M.; Knipscheer, Puck; Kanaar, Roland; Zelensky, Alex N.

doi:10.1016/j.celrep.2019.05.096

Cited by 55 publications

(120 citation statements)

References 71 publications

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“…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.…”

Section: Mice With the Hsf2bp S167l Variant Show A Partial Reduction supporting

confidence: 90%

“…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.…”

Section: Introductionsupporting

confidence: 90%

“…We next sought to understand how the HSF2BP pathogenic variant is mediating the observed meiotic alteration. HSF2BP has been shown to bind BRCA2, an essential protein for homologous meiotic recombination (Martinez et al, 2016;Sharan et al, 2004), in a direct manner tnatahrough its tryptophane at position 200 and the C-term (Gly2270-Thr2337) (Brandsma PhD thesis 2016;(Brandsma et al, 2019)). Given the impossibility to detect endogenous BRCA2 by IF in mouse spermatocytes, we carried out co-localization/interaction assays in a heterologous system by transfecting BRCA2-C (C-term) and HSF2BP in U2OS/HEK293T.…”

Section: Mice With the Hsf2bp S167l Variant Show A Partial Reduction mentioning

confidence: 99%

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

Felipe‐Medina¹,

Caburet

Sánchez-Sáez³

et al. 2020

Preprint

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Felipe-Medina et al. describe a missense variant in the meiotic gene HSF2BP in a consanguineous family with Premature Ovarian Insufficiency, and characterize it as an hypormorphic allele, that in vivo impairs its dimerization with a novel meiotic actor, MIDAP/ C19ORF57, and affect recombination at double-strand DNA breaks. AbstractPrimary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with 3 cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene.Functional analysis of the HSF2BP-S167L variant in mouse, compared to a new HSF2BP knock-out mouse showed that it behaves as a hypomorphic allele. HSF2BP-S167L females show reduced fertility with small litter sizes. To obtain mechanistic insights, we identified C19ORF57/MIDAP as a strong interactor and stabilizer of HSF2BP by forming a higherorder macromolecular structure involving BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L mutation showed a strongly decreased expression of both MIDAP and HSF2BP at the recombination nodules. Although HSF2BP-S167L does not affect heterodimerization between HSF2BP and MIDAP, it promotes a lower expression of both proteins and a less proficient activity in replacing RPA by the recombinases RAD51/DMC1, thus leading to a lower frequency of cross-overs. Our results provide insights into the molecular mechanism of two novel actors of meiosis underlying non-syndromic ovarian insufficiency.

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Section: Mice With the Hsf2bp S167l Variant Show A Partial Reduction supporting

confidence: 90%

Section: Introductionsupporting

confidence: 90%

Section: Mice With the Hsf2bp S167l Variant Show A Partial Reduction mentioning

confidence: 99%

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

Felipe‐Medina¹,

Caburet

Sánchez-Sáez³

et al. 2020

Preprint

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“…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.…”

Section: Mrm Facilitates Recruitment Of Rad51 and Dmc1 Recombinases Tmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Takemoto

Tani²,

Takada-Horisawa

et al. 2020

Preprint

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Meiotic recombination is critical for genetic exchange and generation of chiasmata that ensures faithful chromosome segregation during meiosis I. Meiotic recombination is initiated by DNA double-strand break (DSB) followed by multiple processes of DNA repair. The exact mechanisms how recombinases localize to DSB remained elusive. Here we show that MRM/C19orf57 is a new player for meiotic recombination in mice. MRM/C19orf57 associates with ssDNA binding proteins, BRCA2 and MEILB2/HSF2BP, critical recruiters of recombinases onto DSB sites. Disruption of MRM/C19orf57 shows severe impact on DSB repair and male fertility. Remarkably, removal of single stranded DNA (ssDNA) binding proteins from DSB sites is delayed, and reciprocally the loading of RAD51 and DMC1 onto resected ssDNA is impaired in Mrm KO spermatocytes. We propose that MRM/C19orf57 modulates localization of recombinases to meiotic DSB sites through the interaction with the BRCA2-MEILB2/HSF2BP complex during meiotic recombination.Manuscript

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Loss of DNA methylation disrupts syncytiotrophoblast development: Proposed consequences of aberrant germline gene activation

Lea,

Hanna

2023

BioEssays

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DNA methylation is a repressive epigenetic modification that is essential for development and its disruption is widely implicated in disease. Yet, remarkably, ablation of DNA methylation in transgenic mouse models has limited impact on transcriptional states. Across multiple tissues and developmental contexts, the predominant transcriptional signature upon loss of DNA methylation is the de‐repression of a subset of germline genes, normally expressed in gametogenesis. We recently reported loss of de novo DNA methyltransferase DNMT3B resulted in up‐regulation of germline genes and impaired syncytiotrophoblast formation in the murine placenta. This defect led to embryonic lethality. We hypothesize that de‐repression of germline genes in the Dnmt3b knockout underpins aspects of the placental phenotype by interfering with normal developmental processes. Specifically, we discuss molecular mechanisms by which aberrant expression of the piRNA pathway, meiotic proteins or germline transcriptional regulators may disrupt syncytiotrophoblast development.

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HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required for Mouse Spermatogenesis

Cited by 55 publications

References 71 publications

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

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

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

Loss of DNA methylation disrupts syncytiotrophoblast development: Proposed consequences of aberrant germline gene activation

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