HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2

Brandsma, Inger; Sato, Koichi; Rossum-Fikkert, Sari E. van; Reuter, Marcel; Odijk, Hanny; Verkaik, Nicole S.; Tempel, Nathalie van den; Oostra, Anneke B.; Dekkers, Dick H. W.; Bezstarosti, Karel; Demmers, Jeroen; Lebbink, Joyce H.G.; Wyman, Claire; Dorsman, Josephine C.; Gent, Dik C. van; Knipscheer, Puck; Kanaar, Roland; Zelensky, Alex N.

doi:10.1101/438945

Cited by 3 publications

(6 citation statements)

References 77 publications

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“…The meiotic phenotype of Brca2 ∆12-14 is more severe than that of Hsf2bp -/-. Since both HSF2BP-and DMC1-binding domains were deleted, it may be a compound phenocopy of the two respective phenotypes: the sexually dimorphic phenotype of the Hsf2bp knockout (greatly reduced RAD51 and DMC1 foci in the male, but both form in females) 18,20,24 combined with a non-dimorphic Dmc1 knockout phenotype (RAD51 foci still form in both sexes, DMC1 lost) 32,33 . However, RAD51 (and DMC1) foci are not completely ablated in Hsf2bp -/spermatocytes 21,25 .…”

Section: Sexual Dimorphism In Rad51 Loadingmentioning

confidence: 99%

“…We and others have recently discovered that BRCA2 forms a high-affinity complex with the previously uncharacterized protein HSF2BP (also called MEILB2) in mouse embryonic stem (mES) cells and meiocytes [19][20][21][22][23][24] . Mice deficient for HSF2BP are born at Mendelian ratios and have no overt somatic phenotypes, but males are infertile due to meiotic HR failure.…”

Section: Introductionmentioning

confidence: 99%

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Chromosome Pairing Through Tensioned DNA Tethers Revealed by BRCA2 Meiotic Domain Deletion

Koornneef,

van Rossum-Fikkert,

Sleddens-Linkels

et al. 2023

Preprint

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BRCA2 has multiple functional domains that interact with different partners, and is essential for both somatic and meiotic homologous recombination (HR). We created aBrca2Δ12-14mouse model with an internal deletion of the region which we named “the meiotic domain of BRCA2”, as its loss results in complete failure of meiotic HR, while somatic HR is intact. The deletion in the protein includes the HSF2BP-binding motifs (exons 12-13) and the DMC1-binding PhePP domain (exon 14).Brca2Δ12-14mice showed complete infertility in both males and females, with sexually dimorphic features. Recombinase foci (both RAD51 and DMC1) were completely undetectable in mutant spermatocytes, but while DMC1 foci were also absent in mutant oocytes, RAD51 foci numbers were only partially reduced (up to 60% fewer, 20% less intense). The relevance of the PhePP domain for meiotic HR has been controversial, but both the phenotype ofBrca2Δ12-14, and our biochemical data indicate that, along with the BRC repeats of BRCA2, PhePP is both essential and specific for DMC1 loading in meiotic HR, analogous to the C-terminal RAD51-specific TR2/CTRB. Further investigation of DSB end processing inBrca2Δ12-14meiocytes and controls, using super-resolution imaging of RPA and SYCP3 led to discovery of two novel features. First, inBrca2Δ12-14oocytes, but not in the spermatocytes nor wild types, we observed RPA foci as doublets ∼200 nm apart, which could represent DSB end separation. Second, we describe RPA structures that are completely HR-dependent and are indicative of long, double-stranded DNA connections between homologs prior to synapsis. The observations led us to a model for chromosome alignment via multiple, tensed DNA tethers that connect the homologous DNA regions. We propose that in combination with dynamic adjustment of chromatin loops by meiotic cohesins, this is a plausible molecular mechanism to bring the homologs closer and initiate synapsis.

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Section: Sexual Dimorphism In Rad51 Loadingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chromosome Pairing Through Tensioned DNA Tethers Revealed by BRCA2 Meiotic Domain Deletion

Koornneef,

van Rossum-Fikkert,

Sleddens-Linkels

et al. 2023

Preprint

Self Cite

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“…New tools to study the role of BRCA2 in meiosis were recently provided by the discovery that, in mouse meiocytes and embryonic stem cells, BRCA2 functions in complex with two previously uncharacterized germline proteins, HSF2BP (also called MEILB2) and BRME1 (15)(16)(17)(18). The reported phenotypes of three independent Hsf2bp (17)(18)(19) and five independent Brme1 knockout mouse models (16)(17)(18)(19)(20)(21)(22) are nearly identical.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Paradoxically, when HSF2BP is produced ectopically in somatic cancer cells, it suppresses HR instead of supporting it as it does in meiocytes (15,24). We demonstrated genetically and biochemically that this is due to HSF2BP interaction with BRCA2: In cancer cells, formation of a complex between HSF2BP and BRCA2 impedes BRCA2 function during the repair of lesions induced by DNA interstrand crosslinking agents and poly(adenosine 5 0 -diphosphateribose) polymerase (PARP) inhibitors (but not by ionizing radiation or the I-SceI nuclease) (15,24). Evolutionary conservation of the interaction between BRCA2 and HSF2BP allowed us to establish, using Xenopus egg extract interstrand crosslink repair assays, that the presence of HSF2BP leads to DNA crosslink-dependent proteasomal degradation of BRCA2 mediated by the p97 segregase (24), which disassembles ubiquitinated protein aggregates (25,26).…”

Section: Introductionmentioning

confidence: 99%

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BRCA2-HSF2BP oligomeric ring disassembly by BRME1 promotes homologous recombination

Ghouil,

Miron,

Sato

et al. 2023

Sci. Adv.

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In meiotic homologous recombination (HR), BRCA2 facilitates loading of the recombinases RAD51 and DMC1 at the sites of double-strand breaks (DSBs). The HSF2BP-BRME1 complex interacts with BRCA2. Its absence causes a severe reduction in recombinase loading at meiotic DSB. We previously showed that, in somatic cancer cells ectopically producing HSF2BP, DNA damage can trigger HSF2BP-dependent degradation of BRCA2, which prevents HR. Here, we report that, upon binding to BRCA2, HSF2BP forms octameric rings that are able to interlock into a large ring-shaped 24-nucleotide oligomer. Addition of BRME1 leads to dissociation of both of these ring structures and cancels the disruptive effect of HSF2BP on cancer cell resistance to DNA damage. It also prevents BRCA2 degradation during interstrand DNA crosslink repair in Xenopus egg extracts. We propose that, during meiosis, the control of HSF2BP-BRCA2 oligomerization by BRME1 ensures timely assembly of the ring complex that concentrates BRCA2 and controls its turnover, thus promoting HR.

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Heat shock protein 70 (Hsp70) and heat shock transcription factor (Hsf) gene families in

Deng

Liu²,

et al. 2021

Mar. Freshwater Res.

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Genome-wide characterisation and correlation analysis between gene families and environmental stresses are important for understanding the adaptive evolution of marine animals to various environments. Heat shock protein 70 (Hsp70) and heat shock transcription factor (Hsf) are two important gene families that are associated with abiotic stresses and immune responses. In this study, the evolutionary history and function of Hsp70 and Hsf family genes were investigated in Cynoglossus semilaevis through an exhaustive search of all genomic resources. In addition, their regulatory mechanisms and cooperative relationship in marine fishes were investigated in response to various degrees of salinity stress. Gene structure, motif analysis and phylogenetic trees among various organisms provide references for biological and evolutionary studies of these genes. Most Hsp70 genes were upregulated under low salinity stress, especially heat shock protein family A member 5 (hspa5), whereas hsf1 and hsf2 were downregulated. The expression profile of Hsp70 genes under low salinity stress decreased the activity of hsf1 and hsf2, suggesting that transcriptional repression of Hsf occurs when a certain level of Hsp70 is reached. These findings may improve our understanding the regulatory mechanisms between Hsp70 and Hsf gene families in response to environmental stress and provide useful resources for future studies on these gene families.

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HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2

Cited by 3 publications

References 77 publications

Chromosome Pairing Through Tensioned DNA Tethers Revealed by BRCA2 Meiotic Domain Deletion

Chromosome Pairing Through Tensioned DNA Tethers Revealed by BRCA2 Meiotic Domain Deletion

BRCA2-HSF2BP oligomeric ring disassembly by BRME1 promotes homologous recombination

Heat shock protein 70 (Hsp70) and heat shock transcription factor (Hsf) gene families in

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