Affinage

HSF2BP

Heat shock factor 2-binding protein · UniProt O75031

Length
334 aa
Mass
37.6 kDa
Annotated
2026-06-10
11 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSF2BP (MEILB2) is a meiotic recombination factor that controls the loading of BRCA2 and recombinases at programmed double-strand breaks during spermatogenesis, where loss of the mouse gene causes male infertility from a severe homologous recombination defect (PMID:31242413). It binds BRCA2 constitutively through its armadillo repeats, contacting a discrete region between the BRC repeats and the DNA-binding domain of BRCA2 (PMID:31242413), and assembles a stabilizing ternary complex with BRME1, which engages the α-helical N-terminus of HSF2BP to block self-association and is required for BRCA2-HSF2BP stability, synapsis, and crossover formation (PMID:32345962, PMID:32845237). Structurally, BRCA2 binding drives HSF2BP into octameric rings that interlock into 24-mers, oligomers that BRME1 dissolves (PMID:37889963), while the HSF2BP-BRME1 2:2 core forms a parallel four-helical assembly with DNA-binding β-caps that, upon BRCA2 engagement, dimerizes into a V-shaped clamp bridging resected DNA ends to concentrate recombination machinery (PMID:39095423). Ectopic expression of HSF2BP in somatic cells is disruptive: excess protein triggers removal and degradation of BRCA2 and prevents RAD51 loading, sensitizing cells to crosslinking agents and PARP inhibitors, an effect reversed by BRME1 (PMID:31960047, PMID:37889963). Beyond meiosis, HSF2BP binds the transcription factor BNC1 through its C-terminal hydrophobic domain, sequestering it in the cytoplasm and modulating its transcriptional output (PMID:23707421, PMID:41083582), and in hepatocytes it is SUMOylated by UBC9 to drive nuclear translocation and COX6A1-dependent mitochondrial function (PMID:42259788) and upregulates an HSF2/HSP70 axis that suppresses JNK/p38 MAPK signaling during liver injury (PMID:36167792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2013 Medium

    Established the first molecular partner of HSF2BP outside meiosis, showing it can act as a cytoplasmic regulator of a transcription factor rather than purely a nuclear factor.

    Evidence Yeast two-hybrid, Co-IP, reporter assay, and localization in cell lines

    PMID:23707421

    Open questions at the time
    • Physiological context of the BNC1 interaction not defined
    • Mechanism of cytoplasmic retention not resolved
  2. 2019 High

    Defined HSF2BP as a direct, constitutive BRCA2-binding meiotic recombination factor essential for HR during spermatogenesis, anchoring its core function.

    Evidence Reciprocal Co-IP with domain mapping and mouse knockout in embryonic stem cells/germline

    PMID:31242413

    Open questions at the time
    • Did not resolve how the complex is regulated
    • No structural basis for the interaction
  3. 2020 High

    Showed HSF2BP operates within a ternary BRCA2-HSF2BP-BRME1 complex in which BRME1 stabilizes the assembly and prevents HSF2BP self-association, explaining how the complex is held together in vivo.

    Evidence Co-IP/pulldown, domain mapping, and Brme1 knockout mouse with synapsis/crossover phenotypes

    PMID:32345962 PMID:32845237

    Open questions at the time
    • Did not establish the oligomeric state structurally
    • Recruitment order at DSBs unresolved
  4. 2020 High

    Revealed that ectopic HSF2BP is actively disruptive to somatic HR by removing BRCA2 and blocking RAD51 loading, recasting it as a context-dependent inhibitor and potential synthetic-lethality target.

    Evidence Ectopic overexpression, drug sensitivity assays, and biochemical reconstitution in human cells

    PMID:31960047

    Open questions at the time
    • Mechanism of BRCA2 removal not structurally defined at this stage
    • Relevance to endogenous somatic HSF2BP levels unclear
  5. 2023 High

    Provided the structural and functional logic for HSF2BP's dual behavior by showing BRCA2-induced octameric/24-mer rings are the disruptive species and BRME1 dissolves them to rescue HR.

    Evidence Cryo-EM, biochemical reconstitution, and Xenopus egg extract ICL repair assay

    PMID:37889963

    Open questions at the time
    • How ring formation drives BRCA2 degradation not fully mechanistic
    • In vivo prevalence of ring states unknown
  6. 2024 High

    Delivered the atomic architecture of the HSF2BP-BRME1 core and a BRCA2-induced V-shaped clamp, providing a physical model for tethering resected DNA ends during meiotic recombination.

    Evidence X-ray crystallography of the 2:2 and 2:4:4 complexes with in vivo recruitment validation

    PMID:39095423

    Open questions at the time
    • Direct demonstration of DNA bridging at native DSBs not shown
    • Interplay between clamp and ring states not reconciled
  7. 2022 Medium

    Linked HSF2BP to hepatic stress signaling via an HSF2/HSP70 axis that dampens JNK/p38 MAPK, extending its role into non-meiotic tissue protection.

    Evidence Knockout and transgenic mouse models with siRNA epistasis and Western blotting

    PMID:36167792

    Open questions at the time
    • Direct molecular target connecting HSF2BP to HSF2/HSP70 not identified
    • Single lab
  8. 2025 Medium

    Mapped the BNC1-binding determinant to the HSF2BP C-terminal hydrophobic domain and connected it to TGF-β/SMAD3 signaling in cancer, refining the earlier BNC1 interaction.

    Evidence Co-IP, domain mapping, and in vivo tumor model in lung adenocarcinoma cells

    PMID:41083582

    Open questions at the time
    • Whether BNC1 binding competes with BRCA2/BRME1 binding unknown
    • Single lab
  9. 2026 Medium

    Identified UBC9-mediated SUMOylation as a post-translational switch driving HSF2BP nuclear translocation and COX6A1-dependent mitochondrial function in hepatocytes.

    Evidence Co-IP, hepatocyte-specific OE/KO mice, and pharmacological SUMOylation modulation with metabolic assays

    PMID:42259788

    Open questions at the time
    • SUMO acceptor site on HSF2BP not mapped
    • Connection between SUMOylation and meiotic function untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HSF2BP's meiotic recombination role is mechanistically related to its hepatic, mitochondrial, and transcriptional functions—and whether these reflect distinct regulatory states of one protein—remains unresolved.
  • No unifying model linking HR clamp activity to liver/mitochondrial roles
  • Tissue-specific partner switching not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-73894 DNA Repair 3
Partners
BNC1BRCA2BRME1PALB2RAD51RPAUBC9
Complex memberships
BRCA2-HSF2BP-BRME1 ternary complexHSF2BP-BRME1 2:2 core complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 HSF2BP directly interacts with BRCA2, forming a constitutive complex in mouse embryonic stem cells. The interaction maps to armadillo repeats in HSF2BP and a 68-amino acid region (Gly2270-Thr2337) between the BRC repeats and the DNA binding domain of BRCA2 (encoded by exons 12 and 13). Inactivation of mouse Hsf2bp causes male infertility due to a severe HR defect during spermatogenesis. Co-immunoprecipitation, domain mapping, mouse knockout Cell reports High 31242413
2020 HSF2BP (MEILB2) forms a ternary complex with BRCA2 and BRME1 (C19ORF57). BRME1 binds the α-helical N-terminus of MEILB2/HSF2BP, preventing MEILB2 self-association and stabilizing the complex. BRCA2 binds the C-terminus of MEILB2/HSF2BP. In Brme1-/- mice, the BRCA2-MEILB2 complex is destabilized, causing defects in DSB repair, homolog synapsis, and crossover formation. Co-immunoprecipitation, pulldown, mouse knockout, immunofluorescence Nature communications High 32345962
2020 Ectopic production of HSF2BP in non-germline human cells sensitizes them to ICL-inducing agents (mitomycin C and cisplatin) and PARP inhibitors. Biochemical reconstitution showed that excess HSF2BP compromises HR by triggering removal of BRCA2 from the ICL site and preventing RAD51 loading, recapitulating a Fanconi anemia-like cellular phenotype. Ectopic overexpression in human cells, cellular sensitivity assays, biochemical reconstitution, immunofluorescence Nucleic acids research High 31960047
2020 BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA, and PALB2. The HSF2BP-S167L missense variant behaves as a hypomorphic allele; meiocytes bearing this variant show strongly decreased staining of both HSF2BP and BRME1 at recombination nodules and a reduced number of RAD51/DMC1 foci, leading to fewer crossovers. Co-immunoprecipitation, mouse knock-in model, immunofluorescence eLife High 32845237
2013 HSF2BP interacts with the zinc finger transcription factor BNC1 (Basonuclin 1), inhibits BNC1 transcriptional activity without affecting its expression level, and causes striking redistribution of BNC1 from the nucleus to the cytoplasm upon co-expression. Yeast two-hybrid, co-immunoprecipitation, transcriptional reporter assay, subcellular localization (microscopy) FEBS letters Medium 23707421
2022 HSF2BP upregulates expression of HSF2 and HSP70, and inhibits activation of JNK1/2 and p38 MAPK in hepatocytes. HSP70 siRNA pretreatment abolished the effect of HSF2BP on the MAPK pathway, establishing a HSF2BP→HSP70→MAPK regulatory axis in acute liver injury. Knockout and transgenic mouse models, siRNA knockdown, Western blotting Cell death & disease Medium 36167792
2023 Upon binding to BRCA2, HSF2BP forms octameric rings that interlock into a large ring-shaped 24-mer. Addition of BRME1 dissociates both ring structures, cancels the disruptive effect of HSF2BP on HR in cancer cells, and prevents BRCA2 degradation during ICL repair in Xenopus egg extracts. Cryo-EM/electron microscopy structural analysis, biochemical reconstitution, Xenopus egg extract assay Science advances High 37889963
2024 Crystal structure of the MEILB2(HSF2BP)-BRME1 2:2 core complex reveals a parallel four-helical assembly with an N-terminal β-cap that binds DNA and a MEILB2 coiled-coil bridging to C-terminal ARM domains. Upon BRCA2 binding, MEILB2-BRME1 2:2 complexes dimerize into a V-shaped 2:4:4 complex with the β-caps separated by ~25 nm, suggesting HSF2BP-BRME1 functions as a DNA clamp connecting resected DNA ends to facilitate meiotic recombination. X-ray crystallography, in vivo validation of complex recruitment Nature communications High 39095423
2022 Two novel HSF2BP missense variants (C128R and L186P) impair nuclear localization of HSF2BP and reduce its DNA repair capacity in vitro. In vitro functional assay, subcellular localization analysis Frontiers in cell and developmental biology Low 35174157
2025 HSF2BP binds directly to BNC1, with the C-terminal hydrophobic domain of HSF2BP being essential for this interaction, modulating BNC1-dependent TGF-β and SMAD3 signaling in lung adenocarcinoma cells. Co-immunoprecipitation, domain mapping, overexpression/knockdown in cell lines, in vivo mouse tumor model Scientific reports Medium 41083582
2026 HSF2BP undergoes SUMOylation through interaction with UBC9, which promotes HSF2BP nuclear translocation and upregulation of COX6A1 (a mitochondrial complex IV subunit), thereby enhancing mitochondrial function and reducing hepatic lipid accumulation. Pharmacological inhibition of SUMOylation abolishes the protective effect, while UBC9 overexpression or SUMO activator N106 treatment rescues it. Co-immunoprecipitation (UBC9 interaction), hepatocyte-specific overexpression/knockout mouse models, pharmacological inhibition/activation of SUMOylation, Western blotting, metabolic assays Cell death & disease Medium 42259788

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required for Mouse Spermatogenesis. Cell reports 44 31242413
2020 The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells. Nature communications 42 32345962
2020 A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1. eLife 32 32845237
2020 HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair. Nucleic acids research 19 31960047
2022 HSF2BP protects against acute liver injury by regulating HSF2/HSP70/MAPK signaling in mice. Cell death & disease 15 36167792
2013 HSF2BP represses BNC1 transcriptional activity by sequestering BNC1 to the cytoplasm. FEBS letters 13 23707421
2022 Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency. Frontiers in cell and developmental biology 6 35174157
2024 MEILB2-BRME1 forms a V-shaped DNA clamp upon BRCA2-binding in meiotic recombination. Nature communications 3 39095423
2025 HSF2BP modulates lung adenocarcinoma proliferation and immune microenvironment via BNC1/TGF-β/SMAD3 signaling pathway. Scientific reports 2 41083582
2023 BRCA2-HSF2BP oligomeric ring disassembly by BRME1 promotes homologous recombination. Science advances 2 37889963
2026 SUMOylation-driven nuclear translocation of HSF2BP alleviates MASLD via COX6A1-dependent mitochondrial reprogramming. Cell death & disease 0 42259788

Missed literature

Know a paper Affinage missed for HSF2BP? Flag it for the maintainers and the community.

No submissions yet.