Affinage

IHO1

Interactor of HORMAD1 protein 1 · UniProt Q8IYA8

Length
594 aa
Mass
66.3 kDa
Annotated
2026-06-10
20 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IHO1 (CCDC36), the mammalian ortholog of yeast Mer2/Rec15 and fungal Asy2, is an essential scaffold protein that nucleates the assembly of meiotic DNA double-strand break (DSB) machinery on chromosome axes (PMID:27723721, PMID:29021238). IHO1 directly binds the axis protein HORMAD1, an interaction required for its robust recruitment to unsynapsed axes, and together with the SPO11-auxiliary proteins MEI4 and REC114 it forms chromatin-bound recombinosomes that promote DSB formation (PMID:27723721, PMID:30569039). Structurally, IHO1 forms coiled-coil-based tetramers and engages the pleckstrin-homology (PH) domain of REC114 using the same surface that REC114 employs for TOPOVIBL and ANKRD31, so REC114 acts as a regulatory platform for mutually exclusive interactions, while REC114 itself dimerizes and assembles with MEI4 as a higher-order ternary complex (PMID:37431931, PMID:30569039). This IHO1-REC114-MEI4 accessory network controls the catalytic activity of the SPO11-TOPOVIBL (TOPOVIL) complex that generates programmed DSBs (PMID:36396648). IHO1 seeds and grows DSB-machinery clusters on the axis through its HORMAD1 interaction, a process dependent on DDK-mediated IHO1 phosphorylation, and it anchors PRDM9-marked DSB sites to the axis components HORMAD1 and SYCP3 (PMID:38580643, PMID:38657614). Upstream, meiotic cohesin (STAG3/REC8) promotes IHO1 axis localization, and the SCF-FBXO47 ubiquitin ligase restrains pre-DSB complex accumulation via HORMAD1 turnover (PMID:30853435, PMID:35489071). Once DSBs form, multiple ATM-, ATR-, and PRKDC-dependent negative-feedback pathways locally and globally deplete IHO1 from chromosome axes, limiting further break formation (PMID:33619545, PMID:33842489).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2016 High

    Established the founding link between an axis-bound scaffold and meiotic break formation by showing IHO1 binds HORMAD1 and is required for DSBs and recombinosome assembly with MEI4 and REC114.

    Evidence Co-IP, yeast two-hybrid, immunofluorescence, and mouse knockout with meiotic phenotype

    PMID:27723721

    Open questions at the time
    • Stoichiometry and architecture of the IHO1-containing recombinosome not resolved
    • Mechanism by which recombinosomes activate SPO11 not defined
  2. 2017 Medium

    Placed IHO1 in an evolutionarily conserved DSB-initiation framework by identifying it as the Mer2/Rec15/Asy2 ortholog with conserved roles in recombination, pairing, and chromosome compaction.

    Evidence Genetic and cytological analysis of Mer2 orthologs in Sordaria with sequence conservation

    PMID:29021238

    Open questions at the time
    • Mammalian functions inferred by orthology, not tested in this work
    • Whether pairing/compaction roles transfer to IHO1 unknown
  3. 2017 Medium

    Proposed a route from PRDM9-marked hotspots to the axis-bound machinery by identifying a CXXC1-IHO1 interaction analogous to yeast Spp1-Mer2.

    Evidence Yeast two-hybrid and Co-IP in mouse meiosis

    PMID:28527011

    Open questions at the time
    • Functional consequence inferred by analogy rather than tested directly
    • Whether CXXC1 recruits IHO1 to hotspots in vivo unresolved
  4. 2018 High

    Defined the molecular organization of the accessory complex by reconstituting an IHO1-MEI4-REC114 ternary complex and resolving the REC114 PH-like domain that mediates MEI4 binding.

    Evidence Co-IP in spermatocytes, in vitro reconstitution, and crystallography of REC114 N-terminal domain

    PMID:30569039

    Open questions at the time
    • Atomic-level IHO1-REC114 interface not resolved here
    • Higher-order assembly stoichiometry not determined
  5. 2019 Medium

    Identified upstream axis-recruitment and spatial-patterning inputs to IHO1 through cohesin (STAG3/REC8) dependence and ANKRD31 co-assembly controlling DSB distribution.

    Evidence Mouse knockouts of Stag3 and Ankrd31 with IHO1 co-localization and DSB cytology

    PMID:30853435 PMID:31000436

    Open questions at the time
    • Mechanism by which cohesin promotes IHO1 loading not defined
    • How ANKRD31 directs PAR-localized DSBs at the molecular level unclear
  6. 2021 High

    Revealed DSB-triggered negative feedback that limits the machinery, showing distinct ATM, ATR, and PRKDC pathways locally and globally deplete IHO1 from axes after breaks form.

    Evidence Mouse genetic/pharmacological perturbation of DDR kinases with IHO1 axis quantification, plus zebrafish spo11 mutant analysis

    PMID:33619545 PMID:33842489

    Open questions at the time
    • Direct substrates and phospho-sites driving IHO1 depletion not identified
    • How global vs local depletion is partitioned mechanistically unclear
  7. 2022 Medium

    Connected the IHO1 accessory network to the catalytic core and to its ubiquitin-mediated restraint, mapping REC114-TOPOVIBL coupling and SCF-FBXO47 control of HORMAD1/pre-DSB complex levels.

    Evidence Structural and Co-IP analysis with TOPOVIBL point-mutant knockins and genome-wide DSB mapping; Skp1 cKO with FBXO47-HORMAD1 ubiquitination assays

    PMID:35489071 PMID:36396648

    Open questions at the time
    • Direct IHO1 contribution to TOPOVIL activation not isolated from REC114-TOPOVIBL contact
    • Whether IHO1 itself is a ubiquitination target unknown
  8. 2023 High

    Defined IHO1 oligomeric architecture and the competitive logic of the assembly, showing IHO1 tetramerizes and binds the REC114 PH domain at a surface shared with TOPOVIBL and ANKRD31.

    Evidence AlphaFold2 modeling validated by AUC, SEC-SAXS, pulldowns, and interface mutagenesis

    PMID:37431931

    Open questions at the time
    • In vivo functional consequence of mutually exclusive REC114 binding not tested
    • Dynamics of partner exchange during DSB formation unknown
  9. 2024 High

    Established IHO1 as the seed for cluster biogenesis and the bridge anchoring hotspots to the axis, showing DDK-dependent IHO1 phosphorylation drives axial platform formation and IHO1 tethers PRDM9-marked sites to HORMAD1 and SYCP3.

    Evidence Mouse genetics, DDK chemical inhibition, IHO1 phospho-analysis, ChIP-seq, and co-localization imaging

    PMID:38580643 PMID:38657614

    Open questions at the time
    • DDK phospho-acceptor residues on IHO1 not mapped
    • How IHO1-axis tethering is released during repair not defined
  10. 2026 Low

    Reinforced IHO1 as a direct MEI1 partner with clinical relevance, since azoospermia-associated MEI1 variants disrupt MEI1-IHO1 binding.

    Evidence Co-IP of MEI1 disease variants with IHO1 and other DSB proteins

    PMID:41706353

    Open questions at the time
    • Single Co-IP assay without reciprocal or in vivo validation
    • Functional role of the IHO1-MEI1 interaction in DSB formation not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IHO1 platform assembly is mechanistically coupled to triggering SPO11-TOPOVIBL catalysis, and the precise phospho-regulation governing its loading and feedback removal, remain open.
  • No direct demonstration that IHO1 stimulates SPO11 catalytic activity
  • DDK and DDR-kinase phospho-site maps on IHO1 incomplete
  • Structure of the full axis-bound IHO1 cluster not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005694 chromosome 2
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2
Partners
ANKRD31CXXC1HORMAD1MEI1MEI4REC114SKP1SYCP3
Complex memberships
IHO1-REC114-MEI4 pre-DSB recombinosome

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 IHO1 (CCDC36) directly interacts with HORMAD1 and is essential for meiotic DNA double-strand break (DSB) formation in mice. IHO1 and conserved SPO11-auxiliary proteins MEI4 and REC114 assemble chromatin-bound recombinosomes on meiotic chromosome axes that are predicted activators of DSB formation. HORMAD1 is required for robust recruitment of IHO1 to unsynapsed axes and efficient formation/stabilization of these recombinosomes. Co-immunoprecipitation, yeast two-hybrid, immunofluorescence localization, mouse knockout/loss-of-function with meiotic phenotype readout Nature cell biology High 27723721
2018 IHO1, MEI4, and REC114 form a ternary complex in mouse spermatocytes on the axes of meiotic chromosomes. MEI4 forms a stable complex with REC114, and the REC114 C-terminal domain interacts with the MEI4 N-terminal domain in vitro. The REC114 N-terminal domain has structural similarity to Pleckstrin homology (PH) domains. Co-immunoprecipitation in spermatocytes, in vitro complex reconstitution, X-ray crystallography of REC114 N-terminal domain Life science alliance High 30569039
2017 CXXC1 interacts with IHO1 in mouse meiosis, providing a potential molecular link between PRDM9-marked recombination hotspots and the DSB machinery on the chromosome axis, analogous to the yeast Spp1-Mer2 interaction. Yeast two-hybrid assay, Co-immunoprecipitation Chromosoma Medium 28527011
2017 IHO1 is the mammalian ortholog of yeast Mer2/Rec15 and fungal Asy2, establishing evolutionary conservation of the DSB initiation complex scaffold across fungi, plants, and mammals. In Sordaria, the Mer2 ortholog mediates assembly of recombination-initiation complexes and DSBs, as well as homolog pairing and chromosome compaction. Genetic and cytological analysis of Mer2 mutants in Sordaria, immunolocalization, sequence conservation analysis Genes & development Medium 29021238
2019 ANKRD31 associates with the DSB-promoting protein complex (including IHO1) on meiotic chromosome axes and is required for normal spatiotemporal patterning of DSB formation, including high rates of DSBs at pseudoautosomal regions (PARs). Loss of ANKRD31 causes delayed and redistributed DSB formation and failure of X-Y chromosome recombination. Mouse knockout, immunofluorescence co-localization with IHO1 and other DSB factors, cytological analysis of DSB markers Molecular cell High 31000436
2019 STAG3 (meiotic cohesin) and REC8 promote axis localization of IHO1 (along with HORMAD1 and MEI4) in spermatocytes. STAG3 deficiency reduces IHO1 recruitment to chromosome axes, demonstrating that meiotic cohesin complexes are upstream of IHO1 axis association. Mouse knockout (Stag3-deficient), immunofluorescence localization of IHO1 and associated proteins, genetic epistasis Current biology : CB Medium 30853435
2021 DSBs restrict the DSB machinery via at least four distinct negative feedback pathways in mice: (1) ATM kinase activation by DSBs restricts pre-DSB recombinosome numbers without affecting IHO1 axis levels; (2) ATR kinase locally depletes IHO1 near DSB sites; (3) DSB-enabled homolog synapsis promotes depletion of IHO1 and pre-DSB recombinosomes from synapsed axes; (4) DSBs and three DDR kinases (ATM, ATR, PRKDC) enable stage-specific global depletion of IHO1 from all axes. Mouse genetic models (ATM, ATR, PRKDC inhibition/knockout), immunofluorescence quantification of IHO1 and recombinosome proteins on chromosome axes, epistasis analysis Nucleic acids research High 33619545
2021 In zebrafish spermatocytes, IHO1 dissociation from chromosome axes occurs in a DSB-dependent manner; persistent IHO1 foci are observed in spo11 mutant spermatocytes where no DSBs are formed, while IHO1 signal kinetics are otherwise similar to wild type. Zebrafish spo11 mutant analysis, immunofluorescence localization of Iho1 on chromosome axes Frontiers in cell and developmental biology Medium 33842489
2022 REC114 directly interacts with TOPOVIBL (the SPO11 accessory subunit), and this interaction is required for efficient DSB formation genome-wide. IHO1 is part of the accessory factor network (IHO1-REC114-MEI4-MEI1) controlling TOPOVIL catalytic activity. Point mutations in TOPOVIBL that disrupt REC114 binding strongly reduce DSBs in oocytes and sub-telomeric regions in spermatocytes. Co-immunoprecipitation, structural analysis of conserved interacting domains, mouse point-mutation knockin models, DSB monitoring genome-wide Nature communications High 36396648
2022 SKP1 (subunit of SCF E3 ubiquitin ligase) restrains accumulation of the pre-DSB complex (IHO1-REC114-MEI4) on the meiotic chromosome axis. Loss of SKP1 leads to aberrant IHO1 localization. FBXO47, a meiosis-specific F-box protein, interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and proteasomal degradation, thereby modulating the pre-DSB complex. Mouse conditional knockout of Skp1, co-immunoprecipitation of FBXO47-SKP1-HORMAD1, ubiquitination assay in HEK293T cells, immunofluorescence of IHO1 axis localization Nucleic acids research Medium 35489071
2023 IHO1 forms coiled-coil-based tetramers. IHO1 directly interacts with the PH domain of REC114, recognizing the same surface used by TOPOVIBL and ANKRD31, suggesting REC114 acts as a regulatory platform for mutually exclusive interactions with multiple partners including IHO1. REC114 forms homodimers and assembles with MEI4 as a 2:1 heterotrimer that further dimerizes, constituting a ternary IHO1-REC114-MEI4 complex. AlphaFold2 structural modeling, biochemical characterization (analytical ultracentrifugation, SEC-SAXS, pulldown assays), mutagenesis of interaction interfaces The EMBO journal High 37431931
2024 IHO1 acts as a seed/platform on chromosome axes for biogenesis of DSB-machinery clusters. Axial IHO1 platforms are based on IHO1-HORMAD1 interaction. IHO1 phosphorylation and formation of axial IHO1 platforms are diminished by chemical inhibition of DBF4-dependent kinase (DDK), placing DDK upstream of IHO1 axis association. ANKRD31 enhances both seeding and growth of DSB-machinery clusters independently, providing a complementary pathway when IHO1-HORMAD1 interaction is disrupted. Mouse genetic models, DDK chemical inhibition, phosphorylation analysis of IHO1, immunofluorescence quantification of IHO1 cluster formation on axes, epistasis with ANKRD31 Nature communications High 38580643
2024 IHO1 anchors DSB sites (marked by PRDM9 binding) to chromosome axis components HORMAD1 and SYCP3. PRDM9 promotes recruitment of MEI4 and IHO1 to chromatin, and IHO1 in turn tethers these sites to the axis. IHO1, HORMAD1, and SYCP3 remain associated at DSB ends during DSB repair. ChIP-seq identification of axis-associated genomic sites, co-localization immunofluorescence, mouse genetic models showing PRDM9-dependent IHO1 and MEI4 recruitment Molecular cell High 38657614
2026 MEI1 variants that cause non-obstructive azoospermia disrupt interactions of MEI1 with IHO1 (as well as ANKRD31, REC114, MEI4), as demonstrated by co-immunoprecipitation assays, establishing that IHO1 is a direct binding partner of MEI1 in the meiotic DSB machinery. Co-immunoprecipitation of MEI1 variants with IHO1 and other meiotic DSB proteins Journal of assisted reproduction and genetics Low 41706353

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Meiotic DNA break formation requires the unsynapsed chromosome axis-binding protein IHO1 (CCDC36) in mice. Nature cell biology 141 27723721
2018 Mouse REC114 is essential for meiotic DNA double-strand break formation and forms a complex with MEI4. Life science alliance 80 30569039
2019 Mouse ANKRD31 Regulates Spatiotemporal Patterning of Meiotic Recombination Initiation and Ensures Recombination between X and Y Sex Chromosomes. Molecular cell 74 31000436
2017 The PRDM9 KRAB domain is required for meiosis and involved in protein interactions. Chromosoma 66 28527011
2017 Asy2/Mer2: an evolutionarily conserved mediator of meiotic recombination, pairing, and global chromosome compaction. Genes & development 62 29021238
2018 The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells. Scientific reports 47 30333500
2022 TOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks. Nature communications 36 36396648
2019 Prdm9 and Meiotic Cohesin Proteins Cooperatively Promote DNA Double-Strand Break Formation in Mammalian Spermatocytes. Current biology : CB 31 30853435
2021 Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice. Nucleic acids research 26 33619545
2022 SCF ubiquitin E3 ligase regulates DNA double-strand breaks in early meiotic recombination. Nucleic acids research 25 35489071
2023 Characterization of the REC114-MEI4-IHO1 complex regulating meiotic DNA double-strand break formation. The EMBO journal 18 37431931
2024 Principles of chromosome organization for meiotic recombination. Molecular cell 16 38657614
2021 Sycp1 Is Not Required for Subtelomeric DNA Double-Strand Breaks but Is Required for Homologous Alignment in Zebrafish Spermatocytes. Frontiers in cell and developmental biology 15 33842489
2024 Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes. Nature communications 12 38580643
2022 FIGNL1 is a potential biomarker of cisplatin resistance in non-small cell lung cancer. The International journal of biological markers 7 35791674
2025 Exome sequencing identifies genes for socioeconomic status in 350,770 individuals. Proceedings of the National Academy of Sciences of the United States of America 4 39772748
2023 Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes. bioRxiv : the preprint server for biology 3 38077023
2026 Crocins Ameliorate Experimental Immune Checkpoint Inhibitor-Related Myocarditis by Targeting the Hpx/Nrf2/HO-1 Pathway. International journal of molecular sciences 0 41596558
2026 A common cause of non-obstructive azoospermia: biallelic MEI1 variants and implications for infertility diagnostics. Journal of assisted reproduction and genetics 0 41706353
2023 Lymphocyte Expression of Intracellular Cytokines and Heat Shock Proteins in Peripheral Blood of Patients with Atopic Dermatitis. Current pharmaceutical design 0 37594098

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