Affinage

CCNB1IP1

E3 ubiquitin-protein ligase CCNB1IP1 · UniProt Q9NPC3

Length
277 aa
Mass
31.5 kDa
Annotated
2026-06-09
18 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCNB1IP1 (HEI10) is a RING-domain E3 ubiquitin ligase that governs class I (interference-sensitive) crossover formation during meiosis and modulates cyclin B/CDK1 activity in somatic cells (PMID:17784788, PMID:22792078, PMID:17297447). Its catalytic activity is coupled to higher-order self-assembly: a 29-nm rod-like tetramer forms through head-to-head association of two coiled-coil dimers, clustering four RING domains at its centre, and this assembly is required to catalyse K63-linked ubiquitin chains in vitro (PMID:42146605). In meiosis the protein appears on chromosomes during pachynema rather than at early DSB stages, progressing from foci that co-localise with recombination markers to linear signals along the synaptonemal complex central region and finally to discrete foci at future chiasma sites (PMID:22792078, PMID:21779533). Focus formation depends on liquid-liquid phase separation governed by residue Ser70, and HEI10 diffusion along the SC drives a coarsening process that spaces crossover-promoting foci while preserving interference; ubiquitination of the recombination factor RPA1a is one downstream event promoting its degradation (PMID:38134200, PMID:36224180). The RING domain mediates the maturation and turnover of sequential recombination complexes and is essential for male but not female meiosis, while the RXL (putative cyclin-binding) domain oppositely modulates SUMO localisation along the SC, and recruitment to chromosomes requires the upstream partner HEIP1 [PMID:24831702, PMID:38180592, PMID:bio_10.1101_2025.08.25.672081]. Outside meiosis, HEI10 suppresses cell migration and invasion by acting upstream of cyclin B/CDK1, an activity linked to its interaction with the tumor suppressor merlin (NF2), and it controls cyclin B1 ubiquitination and degradation in the G2/M radiation response (PMID:17297447, PMID:16532029, PMID:39849382). In neuroblastoma cells it protects MYCN from FBXW7-mediated degradation within a positive transcriptional feedback loop (PMID:37461251). Loss of HEI10 abolishes chiasmata and causes sterility in both sexes (PMID:17784788).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 Low

    Identifying HEI10 as a chromosomal translocation partner gave the first hint of a disease association before any functional role was known.

    Evidence 3' RACE cloning of an HMGIC-HEI10 fusion cDNA from uterine leiomyoma with radiation hybrid mapping

    PMID:11223542

    Open questions at the time
    • Provides no functional mechanism for HEI10 itself
    • Causal role of the fusion in tumorigenesis not established
  2. 2006 Medium

    Discovery of a direct merlin (NF2) interaction placed HEI10 in a tumor-suppressor signalling context and mapped the binding interfaces.

    Evidence Co-immunoprecipitation, domain mapping, and co-localisation with constitutively open merlin in human cells

    PMID:16532029

    Open questions at the time
    • Functional consequence of the interaction left unresolved
    • Single lab without reciprocal in vivo validation
  3. 2007 High

    Two independent lines of evidence established HEI10 both as an essential meiotic crossover factor and as a somatic suppressor of cell invasion acting through cyclin B/CDK1.

    Evidence ENU mutant cytological analysis of mouse spermatocytes/oocytes; siRNA knockdown with migration/invasion assays and Cdk1/cyclin B inhibitor rescue in human cells

    PMID:17297447 PMID:17784788

    Open questions at the time
    • Direct ubiquitin ligase activity not biochemically demonstrated
    • Substrate of the proposed cyclin B ligase activity not identified
    • Molecular link between merlin and the cyclin B axis untested
  4. 2010 Medium

    Pachytene-stage chromosome loading plus a SUMO2 interaction screen reframed HEI10 as a crossover-maturation factor potentially acting as a SUMO ligase.

    Evidence Immunofluorescence localisation with specific antibody and yeast two-hybrid screen against sumoylation-consensus proteins

    PMID:21779533

    Open questions at the time
    • SUMO E3 ligase activity inferred but not reconstituted
    • Y2H interactions not validated by reciprocal binding
  5. 2012 High

    Rice work pinned HEI10 specifically to the class I crossover pathway and revealed its dynamic focus-to-line-to-focus localisation pattern.

    Evidence Map-based cloning and immunolocalisation on meiotic chromosomes in a hei10 null mutant

    PMID:22792078

    Open questions at the time
    • Mechanism converting linear signal to discrete foci unknown
    • Substrates ubiquitinated during maturation not identified
  6. 2014 High

    Domain-specific mutagenesis dissected opposing roles of the RING and RXL domains in recombination-complex turnover and SUMO distribution.

    Evidence Null, RING-binding, and RXL domain mutant analysis with immunolocalisation and recombination nodule ultrastructure in Sordaria

    PMID:24831702

    Open questions at the time
    • Direct catalytic targets of the RING domain not defined
    • Biochemical basis of RXL-dependent SUMO modulation unresolved
  7. 2022 High

    Genetic epistasis showed HEI10 dosage and SC diffusion drive a coarsening process that sets crossover number and spacing.

    Evidence HEI10 overexpression lines and HEI10-OE x zyp1 double-mutant crossover/interference analysis in Arabidopsis

    PMID:36224180

    Open questions at the time
    • Physical mechanism of coarsening not directly observed
    • Conservation of dosage effect in animals untested
  8. 2023 High

    Phase separation and substrate identification connected HEI10 condensation to its catalytic crossover function and to MYCN stability in cancer.

    Evidence LLPS assay, Ser70Phe mutagenesis, IP-MS, and ubiquitination assay in Arabidopsis; Co-IP, ubiquitination IP, ChIP, and luciferase reporter in neuroblastoma cells

    PMID:37461251 PMID:38134200

    Open questions at the time
    • Whether RPA1a ubiquitination is conserved beyond plants unknown
    • Direct catalytic basis of MYCN protection (competition vs. enzymatic) not fully separated
  9. 2024 Medium

    Condensation requirement, sex-specific RING dependence, and new interactors refined how HEI10 assembly and partners drive meiosis.

    Evidence Temperature-sensitive aggregation mutant (HEI10tfs2) and RING-truncation complementation in rice with Y2H against RPT4/SRFP1

    PMID:38169508 PMID:38180592

    Open questions at the time
    • Basis of sex-specific RING requirement unexplained
    • RPT4/SRFP1 interactions not validated beyond Y2H
  10. 2025 Medium

    Identification of upstream regulators and a radiation-response substrate connected HEI10 recruitment and cyclin B1 control to physiological pathways.

    Evidence Heip1 knockout immunolocalisation and Co-IP in mouse; ubiquitination IP with rescue and ESR1/AdipoR1 transcriptional analysis in somatic cells

    PMID:39849382 PMID:bio_10.1101_2025.08.25.672081

    Open questions at the time
    • Mechanism by which HEIP1 nucleates HEI10/RNF212 loading unresolved
    • HEIP1 finding is a preprint awaiting peer review
    • Direct cyclin B1 ubiquitination by HEI10 versus indirect effect not fully separated
  11. 2026 High

    A crystal structure established the architectural basis linking higher-order self-assembly to E3 ligase catalysis.

    Evidence Crystal structure, structure-guided mutagenesis, and in vitro ubiquitin ligase assay of human HEI10 (preprint)

    PMID:42146605

    Open questions at the time
    • Whether meiotic foci adopt the same tetrameric architecture in vivo untested
    • Substrate-specifying determinants of the assembled ligase not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HEI10's catalytic assembly, phase separation, and substrate choice are integrated to select discrete crossover sites and how these mechanisms translate to its somatic cyclin B/MYCN roles remain unresolved.
  • No unified model linking in vitro tetramer assembly to in vivo foci
  • Full substrate repertoire of the E3 ligase undefined
  • Relationship between meiotic and oncogenic functions unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2
Partners
FBXW7HEIP1MYCNNF2RNF212RPA1ARPT4SRFP1
Complex memberships
synaptonemal complex central region

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2026 Human HEI10 (CCNB1IP1) has E3-ubiquitin ligase activity that depends on its higher-order assembly. Crystal structure reveals a 29-nm rod-like tetramer formed through head-to-head association of two coiled-coil dimers, clustering four RING domains at the molecular centre. HEI10 tetramers self-assemble into fibrous and spherical higher-order structures via RING, coiled-coil, and C-terminal interfaces. Structure-guided mutants show higher-order assembly is required for HEI10 to catalyse K63-linked ubiquitin chain formation in vitro. Crystal structure determination, in vitro ubiquitin ligase assay, structure-guided mutagenesis bioRxivpreprint High 42146605
2007 Mouse HEI10 (Ccnb1ip1/mei4) is required for meiotic crossing over; loss-of-function causes absence of chiasmata, failure of CDK2 and mismatch repair protein association with chromosome cores, premature bivalent separation at diplotene, and sterility in both sexes. The protein is identified as a putative B-type cyclin E3 ubiquitin ligase. ENU mutagenesis, genetic mapping, splice-site mutation characterisation, cytological analysis of spermatocytes/oocytes PLoS genetics High 17784788
2012 Rice HEI10 is required specifically for class I (interference-sensitive) crossover formation but not for early recombination events or synaptonemal complex assembly. HEI10 protein first appears as foci co-localising with MER3, then extends as linear signals along ZEP1-marked SC central regions, and finally restricts to prominent foci at chiasma sites, indicating a dynamic role in crossover intermediate maturation. Map-based cloning, immunolocalisation on meiotic chromosomes, cytological analysis of hei10 mutant PLoS genetics High 22792078
2010 CCNB1IP1 protein appears on meiotic chromosomes during pachynema (not leptotene), implicating it in crossover intermediate maturation rather than early DSB specification. Yeast two-hybrid screen identified interaction with SUMO2 and proteins enriched for sumoylation consensus sites, suggesting CCNB1IP1 functions as an E3 SUMO ligase in meiotic cells. Immunofluorescence with specific antibody (localization), yeast two-hybrid screen Genes Medium 21779533
2014 In Sordaria, Hei10 makes three successive types of foci along SC central regions. The RING domain mediates development and turnover of sequential recombination complexes and positively modulates SUMO localisation along SCs. The RXL (putative cyclin-binding) domain negatively modulates SUMO localisation. Null, RING-binding, and RXL domain mutants show distinct defects, establishing that both domains are required for Hei10's pro-crossover function. Null and domain-specific mutant analysis (RING, RXL), immunolocalisation, ultrastructural analysis of recombination nodules Genes & development High 24831702
2007 HEI10 depletion in human cells increases cell migration and invasion and post-transcriptionally upregulates promotility proteins including p130Cas, paxillin, Cdk1, and cyclin B2. Specific inhibition of Cdk1/cyclin B activity reverses the motility and invasion phenotype of HEI10-depleted cells, placing HEI10 upstream of cyclin B/Cdk1 in suppressing cell invasion. siRNA knockdown, migration/invasion assays, immunoblotting, pharmacological inhibition of Cdk1/cyclin B Oncogene Medium 17297447
2006 HEI10 physically interacts with the tumor suppressor merlin (NF2); the interaction is mediated by the alpha-helical domain of merlin and the coiled-coil domain of HEI10 and requires conformational opening of merlin. HEI10 and merlin show partial cell cycle-dependent and adhesion-dependent subcellular co-localisation. Expression of a constitutively open merlin construct affects HEI10 protein integrity. Co-immunoprecipitation, domain-mapping, immunofluorescence co-localisation, transfection of constitutively open merlin Oncogene Medium 16532029
2023 Arabidopsis HEI10 forms foci on chromatin via liquid-liquid phase separation (LLPS) dependent on residue Ser70; a HEI10S70F allele abolishes LLPS and class I CO formation. HEI10 ubiquitinates RPA1a (identified by immunoprecipitation-mass spectrometry as a HEI10-interacting protein), promoting RPA1a degradation. HEI10 is also required for condensation of other class I CO factors. LLPS assay, site-directed mutagenesis (Ser70Phe), immunoprecipitation-mass spectrometry, ubiquitination assay, immunolocalisation PNAS High 38134200
2023 CCNB1IP1 physically interacts with MYCN (co-immunoprecipitation), protects MYCN from ubiquitination-mediated degradation by competing with FBXW7 for MYCN binding, and does so in a C-terminal domain-dependent manner. MYCN in turn directly transcribes CCNB1IP1 (ChIP + luciferase assay), establishing a positive feedback loop. Co-immunoprecipitation, ubiquitination IP assay, dual-luciferase reporter, chromatin immunoprecipitation, gain/loss-of-function experiments Clinical and translational medicine Medium 37461251
2025 CCNB1IP1 regulates ubiquitination and degradation of cyclin B1, modulating G2/M phase arrest after radiation. ESR1 (estrogen receptor 1) acts as a transcription factor that inhibits CCNB1IP1 transcription; AdipoR1 promotes ESR1 nuclear translocation, thereby suppressing CCNB1IP1 and increasing cyclin B1 levels. Ubiquitination IP assay, rescue experiment, transcription factor database analysis combined with AdipoR1 transcriptome sequencing, nuclear translocation imaging Molecular medicine Medium 39849382
2022 Overexpression of HEI10 in Arabidopsis increases crossover number while maintaining interference and sexual dimorphism. Combining HEI10 overexpression with zyp1 (synaptonemal complex) mutation produces a massive synergistic increase in crossovers, supporting a model in which HEI10 diffusion along the SC drives a coarsening process that spaces crossover-promoting foci. HEI10 overexpression lines, genetic analysis of crossover number and interference, double-mutant epistasis (HEI10-OE × zyp1) Nature communications High 36224180
2024 Rice HEI10 containing a point mutation (Leu→Phe, HEI10tfs2) fails to form nuclear dot-like aggregates at high temperature, resulting in univalent formation and meiotic failure; aggregation is restored at low temperature, restoring fertility. Yeast two-hybrid assays showed HEI10 interacts with RPT4 and SRFP1 (proteasome/ubiquitin-related proteins); aggregation of RPT4 and SRFP1 into foci also depends on HEI10. EMS mutagenesis, genetic complementation, transient expression aggregation assay (tobacco), yeast two-hybrid The Plant journal Medium 38169508
2024 Rice HEI10 truncated at its N-terminus (lacking the RING domain, sh1 allele) localises correctly to the nucleus and retains protein-protein interaction capacity sufficient to partially restore female fertility in hei10 null lines, but completely fails to support male fertility, demonstrating that the RING domain is essential for male but not female meiosis. Genetic complementation, allelic tests, nuclear localisation imaging, fertility assays in hei10 null background Rice Medium 38180592
2025 Mouse HEIP1 directly interacts with HEI10 (co-immunoprecipitation) and is required to recruit HEI10, RNF212, and RNF212B to meiotic chromosomes; loss of HEIP1 abolishes crossovers and causes sterility in both sexes, placing HEIP1 upstream of HEI10 in the pro-crossover pathway. Co-immunoprecipitation, immunolocalisation in Heip1 knockout, genetic analysis of fertility bioRxivpreprint Medium bio_10.1101_2025.08.25.672081
2001 In a uterine leiomyoma, HEI10 (at 14q11) is fused to the HMGIC gene (at 12q15) such that the first two exons of HMGIC (encoding DNA-binding domains) are joined to the 3' portion of HEI10, identifying HEI10 as a chromosomal translocation partner. 3' RACE cloning of fusion cDNA, radiation hybrid mapping Japanese journal of cancer research Low 11223542

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 The role of rice HEI10 in the formation of meiotic crossovers. PLoS genetics 120 22792078
2007 Mutation in mouse hei10, an e3 ubiquitin ligase, disrupts meiotic crossing over. PLoS genetics 100 17784788
2014 E3 ligase Hei10: a multifaceted structure-based signaling molecule with roles within and beyond meiosis. Genes & development 85 24831702
2022 Joint control of meiotic crossover patterning by the synaptonemal complex and HEI10 dosage. Nature communications 75 36224180
2007 HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins. Oncogene 34 17297447
2010 Evidence Implicating CCNB1IP1, a RING Domain-Containing Protein Required for Meiotic Crossing Over in Mice, as an E3 SUMO Ligase. Genes 32 21779533
2001 Fusion of a sequence from HEI10 (14q11) to the HMGIC gene at 12q15 in a uterine leiomyoma. Japanese journal of cancer research : Gann 31 11223542
2006 A functional association between merlin and HEI10, a cell cycle regulator. Oncogene 24 16532029
2023 HEI10 is subject to phase separation and mediates RPA1a degradation during meiotic interference-sensitive crossover formation. Proceedings of the National Academy of Sciences of the United States of America 10 38134200
2024 HEI10 coarsening, chromatin and sequence polymorphism shape the plant meiotic recombination landscape. Current opinion in plant biology 8 38838583
2024 A point mutation in the meiotic crossover formation gene HEI10/TFS2 leads to thermosensitive genic sterility in rice. The Plant journal : for cell and molecular biology 5 38169508
2023 CCNB1IP1 prevents ubiquitination-mediated destabilization of MYCN and potentiates tumourigenesis of MYCN-amplificated neuroblastoma. Clinical and translational medicine 5 37461251
2019 G-quadruplex-forming GGA repeat region functions as a negative regulator of the Ccnb1ip1 enhancer. Bioscience, biotechnology, and biochemistry 3 31062645
2024 Cis-Regulatory Evolution of CCNB1IP1 Driving Gradual Increase of Cortical Size and Folding in primates. bioRxiv : the preprint server for biology 2 39713381
2025 AdipoR1 enhances the radiation resistance via ESR1/CCNB1IP1/cyclin B1 pathway in hepatocellular carcinoma cells. Molecular medicine (Cambridge, Mass.) 1 39849382
2024 The RING Domain of Rice HEI10 is Essential for Male, But Not Female Fertility. Rice (New York, N.Y.) 1 38180592
2022 The effect of Ccnb1ip1 insulator on monoclonal antibody expression in Chinese hamster ovary cells. Molecular biology reports 1 35076847
2026 Molecular architecture of meiotic pro-crossover factor HEI10 reveals coupling of higher-order assembly and ubiquitin chain formation. bioRxiv : the preprint server for biology 0 42146605

Missed literature

Know a paper Affinage missed for CCNB1IP1? Flag it for the maintainers and the community.

No submissions yet.