Affinage

IHO1

Interactor of HORMAD1 protein 1 · UniProt Q8IYA8

Round 2 corrected
Length
594 aa
Mass
66.3 kDa
Annotated
2026-04-28
40 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IHO1 (CCDC36/Mer2 ortholog) is the principal axis-anchoring platform for pre-DSB recombinosomes in mammalian meiosis, nucleating heterooligomeric IHO1–REC114–MEI4 complexes on chromosome cores to activate SPO11/TOPOVIBL-dependent DNA double-strand break formation required for homologous chromosome pairing (PMID:27723721, PMID:30569039, PMID:37431931). IHO1 forms coiled-coil-based tetramers and directly binds the PH domain of REC114, which in turn bridges to the catalytic TOPOVIL complex and to mutually exclusive partners ANKRD31 and TOPOVIBL (PMID:37431931, PMID:36396648). Recruitment of IHO1 to unsynapsed axes depends on HORMAD1, meiotic cohesins (REC8–STAG3), and DDK-mediated phosphorylation, while PRDM9-bound sites promote IHO1 and MEI4 loading onto chromatin (PMID:27723721, PMID:30853435, PMID:38580643, PMID:38657614). Once DSBs are formed, at least four feedback pathways—mediated by ATM, ATR, PRKDC, and synapsis-coupled axis remodeling—progressively deplete IHO1 from synapsed axes, and SCF-FBXO47-directed ubiquitination of HORMAD1 further restrains the pre-DSB complex, ensuring appropriate DSB number and distribution (PMID:33619545, PMID:35489071).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2016 High

    Identification of IHO1 as a HORMAD1 interactor essential for meiotic DSB formation established the first known molecular link between the chromosome axis protein HORMAD1 and the SPO11-accessory DSB machinery in mammals.

    Evidence Co-IP, yeast two-hybrid, immunofluorescence, and Iho1-knockout mouse showing complete loss of DSBs

    PMID:27723721

    Open questions at the time
    • Structural basis of IHO1–HORMAD1 interaction unknown
    • Whether IHO1 has roles beyond DSB initiation not tested
    • Mechanism linking HORMAD1 to IHO1 axis loading unresolved
  2. 2017 Medium

    Discovery that CXXC1 interacts with IHO1, paralleling the yeast Spp1–Mer2 axis-tethering mechanism, suggested a conserved loop-axis tethering module connecting PRDM9-marked hotspots to the DSB machinery on axes.

    Evidence Yeast two-hybrid assay detecting CXXC1–IHO1 interaction

    PMID:28527011

    Open questions at the time
    • Interaction not confirmed by reciprocal Co-IP or in vivo disruption
    • Functional consequence of disrupting the CXXC1–IHO1 link not tested in mice
  3. 2017 High

    Analysis of the fungal ortholog Mer2 revealed conserved roles extending beyond DSB formation to homolog juxtaposition, recombination complex transfer, and chromosome compaction, broadening the functional repertoire attributable to IHO1-family proteins.

    Evidence Thirteen Sordaria mer2 mutants with sequential cytological and functional assays

    PMID:29021238

    Open questions at the time
    • Whether mammalian IHO1 retains the compaction and SC-transfer roles demonstrated for fungal Mer2 is untested
    • SUMOylation of mammalian IHO1 not examined
  4. 2018 High

    Reconstitution of a stable REC114–MEI4 sub-complex and demonstration that REC114, MEI4, and IHO1 co-immunoprecipitate in vivo defined the tripartite pre-DSB recombinosome and identified REC114's PH-domain fold as a critical interaction surface.

    Evidence Mouse Rec114 knockout, in vitro reconstitution, X-ray crystallography of REC114 C-terminal/MEI4 N-terminal complex

    PMID:30569039

    Open questions at the time
    • Direct IHO1–REC114 binding interface not yet mapped
    • Stoichiometry of the ternary complex unknown
  5. 2019 High

    Placing meiotic cohesins (REC8–STAG3) and ANKRD31 upstream of IHO1 axis loading resolved the hierarchical dependency for pre-DSB complex assembly: cohesins recruit HORMAD1/IHO1, and ANKRD31 ensures timely accumulation especially at the PAR.

    Evidence Mouse knockouts of ANKRD31 and cohesin subunits with direct IHO1 localization readout by immunofluorescence

    PMID:30853435 PMID:31000436

    Open questions at the time
    • Whether ANKRD31 acts directly on IHO1 or indirectly through other axis components not resolved
    • Biochemical mechanism by which cohesins promote IHO1 loading unknown
  6. 2021 High

    Dissection of four distinct negative-feedback pathways—ATM restricting recombinosome numbers, ATR locally depleting IHO1 near DSBs, synapsis removing IHO1 from synapsed axes, and combined ATM/ATR/PRKDC enabling global IHO1 depletion—established IHO1 as the central regulatory target ensuring DSB homeostasis.

    Evidence Mouse kinase mutants and inhibitors with quantitative immunofluorescence of IHO1 on chromosome spreads; zebrafish spo11 mutants showing DSB-dependent IHO1 removal

    PMID:33619545 PMID:33842489

    Open questions at the time
    • Direct phosphorylation sites on IHO1 targeted by ATM/ATR/PRKDC not identified
    • Mechanistic basis of synapsis-coupled IHO1 stripping unresolved
  7. 2022 High

    Structural and genetic evidence that REC114 bridges IHO1-containing pre-DSB recombinosomes to the catalytic TOPOVIL complex via its PH domain, and that SCF-FBXO47 ubiquitinates HORMAD1 to restrain axis-associated IHO1, defined both the downstream catalytic connection and an upstream proteolytic control layer.

    Evidence Crystal structure/AlphaFold of REC114–TOPOVIBL interface with in vivo point-mutant knockins; SKP1/FBXO47 conditional KO with ubiquitination assay and IHO1 immunofluorescence

    PMID:35489071 PMID:36396648

    Open questions at the time
    • Whether IHO1 itself is ubiquitinated or only indirectly regulated via HORMAD1 turnover not determined
    • In vivo stoichiometric competition between TOPOVIBL and ANKRD31 for REC114 PH domain not quantified
  8. 2023 High

    Determination that IHO1 forms coiled-coil tetramers and that its REC114-binding surface is shared with TOPOVIBL and ANKRD31 revealed the oligomeric architecture of the pre-DSB complex and a mutually exclusive interaction logic governing complex composition.

    Evidence AlphaFold2 modeling, analytical ultracentrifugation, multi-angle light scattering, crosslinking mass spectrometry

    PMID:37431931

    Open questions at the time
    • No high-resolution experimental structure of full-length IHO1 tetramer
    • How mutually exclusive interactions are dynamically regulated in vivo is unclear
  9. 2024 High

    Super-resolution imaging and DDK inhibition demonstrated that DDK-dependent phosphorylation of IHO1 seeds axial platforms from which DSB-machinery clusters grow, with ANKRD31 providing a parallel seeding route when IHO1–HORMAD1 interaction is abolished, and PRDM9-bound sites promoting IHO1/MEI4 chromatin recruitment.

    Evidence IHO1–HORMAD1 interaction-disrupting mouse mutants, DDK chemical inhibition, super-resolution microscopy, ChIP-seq for IHO1 and MEI4

    PMID:38580643 PMID:38657614

    Open questions at the time
    • Specific DDK phosphorylation sites on IHO1 not mapped
    • Whether IHO1 persists at DSB repair intermediates functionally or as a passive marker is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the identification of direct phosphorylation sites on IHO1 targeted by DDK, ATM, and ATR; whether IHO1 has post-DSB functional roles (as suggested for fungal Mer2) beyond serving as a platform for DSB initiation; and how the mutually exclusive REC114–partner interactions are dynamically coordinated in vivo.
  • No phosphosite mapping on mammalian IHO1
  • Post-DSB roles of IHO1 in mammals untested
  • No high-resolution experimental structure of intact IHO1 tetramer

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005694 chromosome 7
Pathway
R-HSA-1474165 Reproduction 6 R-HSA-73894 DNA Repair 4
Partners
ANKRD31CXXC1HORMAD1MEI1MEI4REC114TOPOVIBL
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) was identified as a direct interactor of HORMAD1 and shown to be essential for meiotic DNA double-strand break (DSB) formation in mice. IHO1, together with SPO11-auxiliary proteins MEI4 and REC114, assembles chromatin-bound recombinosomes (pre-DSB complexes) on meiotic chromosome axes. HORMAD1 is required for robust recruitment of IHO1 to unsynapsed axes, and this HORMAD1-IHO1 interaction provides a mechanism for selective promotion of DSB formation along unsynapsed chromosome axes. Co-immunoprecipitation, yeast two-hybrid, cytological localization (immunofluorescence), mouse knockout Nature cell biology High 27723721
2017 CXXC1, a member of the COMPASS complex and ortholog of yeast Spp1, interacts with IHO1. This interaction was identified by yeast two-hybrid and suggests that the molecular link between DSB sites (via PRDM9-CXXC1) and the DSB machinery on the chromosome axis (via IHO1) is conserved in mouse meiosis. Yeast two-hybrid assay Chromosoma Medium 28527011
2017 Mer2 (the IHO1 ortholog in Sordaria/fungi) is evolutionarily conserved from fungi to plants (PRD3/PAIR1) and mammals (IHO1). Beyond its role in DSB formation, Mer2 functions in homolog spatial juxtaposition for pairing, transfer/maintenance of recombination complexes to the synaptonemal complex central region, and global chromosome compaction post-recombination. SUMOylation is implicated in the compaction role. Genetic analysis of 13 mer2 mutants, sequential localization of Mer2 to axis/SC/chromatin in Sordaria, cytological and functional assays Genes & development High 29021238
2018 Mouse REC114 is required for meiotic DSB formation and forms a stable complex with MEI4 and IHO1 in spermatocytes. In vitro, the REC114 C-terminal domain forms a stable complex with the MEI4 N-terminal domain. The REC114 N-terminal domain has structural similarity to Pleckstrin homology (PH) domains. Mouse knockout, co-immunoprecipitation, in vitro complex reconstitution, X-ray crystallography Life science alliance High 30569039
2019 ANKRD31 is a key component of DSB-promoting protein complexes on meiotic chromosome axes and interacts with the same complexes as IHO1. Loss of ANKRD31 causes genome-wide delay in assembling DSB-promoting proteins (including IHO1) on autosome axes and abolishes the specialized pseudoautosomal region (PAR)-axis domain enriched for DSB-promoting proteins, resulting in failure of X-Y crossover formation. Mouse knockout, immunofluorescence co-localization, chromosome spread analysis Molecular cell High 31000436
2019 PRDM9 interacts with cohesin subunits STAG3 and REC8 in a cooperative relationship that promotes meiotic DSB formation. STAG3 and REC8 promote axis localization of HORMAD1, IHO1, and MEI4, demonstrating that meiotic cohesin complexes are required upstream of IHO1 axis recruitment. Co-immunoprecipitation, genetic epistasis (double mutants), immunofluorescence in spermatocytes Current biology : CB High 30853435
2021 IHO1 serves as the main anchor for pre-DSB recombinosomes (containing MEI4 and REC114) on chromosome axes. DSBs negatively feed back on the DSB machinery through four distinct pathways: (1) ATM activation restricts pre-DSB recombinosome numbers without affecting IHO1 levels; (2) ATR triggers IHO1 depletion locally near DSBs; (3) synapsis (enabled by DSBs) promotes depletion of IHO1 and pre-DSB recombinosomes from synapsed axes; (4) ATM, ATR, and PRKDC together enable stage-specific depletion of IHO1 from all axes. Mouse genetics (kinase inhibitors and mutants), immunofluorescence, chromosome spread analysis Nucleic acids research High 33619545
2021 In zebrafish, Iho1 dissociation from chromosome axes occurs in a DSB-dependent manner, as persistent Iho1 foci are observed in spo11 mutant spermatocytes. This demonstrates that SPO11-dependent DSB formation is required for IHO1 removal from the axis. Zebrafish mutant analysis (sycp1 and spo11 mutants), immunofluorescence Frontiers in cell and developmental biology Medium 33842489
2022 REC114 directly interacts with TOPOVIBL (the SPO11 partner in the TOPOVIL catalytic complex), and point mutations disrupting this interaction strongly reduce DSB activity genome-wide in oocytes and in sub-telomeric regions in spermatocytes. Since REC114 is a direct partner of both IHO1 and TOPOVIBL, REC114 serves as a key bridge linking IHO1-containing pre-DSB recombinosomes to the catalytic TOPOVIL complex. Structural analysis (crystallography/AlphaFold), co-immunoprecipitation, mouse point-mutant knockins, DSB quantification by immunofluorescence and sequencing Nature communications High 36396648
2022 SKP1, a constitutive subunit of the SCF ubiquitin E3 ligase, restrains accumulation of the IHO1-REC114-MEI4 pre-DSB complex on the chromosome axis. Mechanistically, the meiosis-specific F-box protein FBXO47 interacts with SKP1 and HORMAD1, targeting HORMAD1 for polyubiquitination and proteasomal degradation, which in turn modulates the pre-DSB complex including IHO1. Mouse conditional knockout, immunofluorescence, co-immunoprecipitation, ubiquitination assay in HEK293T cells Nucleic acids research High 35489071
2023 IHO1 forms coiled-coil-based tetramers. IHO1 directly interacts with the PH domain of REC114 using the same surface as TOPOVIBL and ANKRD31, indicating mutually exclusive interactions. Combined with AlphaFold2 modeling and biochemical characterization, this demonstrates a ternary IHO1-REC114-MEI4 complex architecture where REC114 acts as a regulatory platform for mutually exclusive partner interactions. AlphaFold2 modeling, biochemical reconstitution, analytical ultracentrifugation, multi-angle light scattering, crosslinking mass spectrometry The EMBO journal High 37431931
2024 Efficient biogenesis of DSB-machinery clusters on chromosome axes requires seeding by axial IHO1 platforms. IHO1 phosphorylation and formation of axial IHO1 platforms are diminished by chemical inhibition of DBF4-dependent kinase (DDK), implicating DDK as a regulator of IHO1 axis assembly. IHO1-HORMAD1 interaction mediates the seeding of DSB-machinery on axes; without this interaction, residual DSBs depend on ANKRD31, which enhances both seeding and growth of DSB-machinery clusters. Mouse genetics (IHO1-HORMAD1 interaction mutants), DDK chemical inhibition, super-resolution microscopy, quantitative immunofluorescence Nature communications High 38580643
2024 PRDM9 binding sites promote recruitment of MEI4 and IHO1 to chromatin. IHO1 in turn anchors DSB sites to the chromosome axis components HORMAD1 and SYCP3. Additionally, IHO1, HORMAD1, and SYCP3 remain associated at DSB ends during DSB repair, linking DSB site identity to axis structure throughout the recombination process. ChIP-seq, immunofluorescence, co-localization analysis in spermatocytes Molecular cell High 38657614
2026 MEI1 variants that cause non-obstructive azoospermia disrupt MEI1 interactions with ANKRD31, IHO1, REC114, and MEI4, as demonstrated by co-immunoprecipitation, establishing that MEI1 is a physical interaction partner of IHO1 within the meiotic DSB machinery. Co-immunoprecipitation in HEK293T cells with patient-derived MEI1 mutants Journal of assisted reproduction and genetics Medium 41706353

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2011 Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 405 22020285
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2016 Meiotic DNA break formation requires the unsynapsed chromosome axis-binding protein IHO1 (CCDC36) in mice. Nature cell biology 135 27723721
2014 Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nature communications 111 24722188
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2016 Pooled-matrix protein interaction screens using Barcode Fusion Genetics. Molecular systems biology 89 27107012
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2018 Mouse REC114 is essential for meiotic DNA double-strand break formation and forms a complex with MEI4. Life science alliance 79 30569039
2019 Mouse ANKRD31 Regulates Spatiotemporal Patterning of Meiotic Recombination Initiation and Ensures Recombination between X and Y Sex Chromosomes. Molecular cell 71 31000436
2017 The PRDM9 KRAB domain is required for meiosis and involved in protein interactions. Chromosoma 66 28527011
2018 An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders. Nature genetics 61 29892012
2019 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. Nature communications 60 31515488
2017 Asy2/Mer2: an evolutionarily conserved mediator of meiotic recombination, pairing, and global chromosome compaction. Genes & development 59 29021238
2019 Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest. Journal of medical genetics 55 31704776
2018 The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells. Scientific reports 47 30333500
2016 An inter-species protein-protein interaction network across vast evolutionary distance. Molecular systems biology 36 27107014
2022 TOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks. Nature communications 34 36396648
2019 Prdm9 and Meiotic Cohesin Proteins Cooperatively Promote DNA Double-Strand Break Formation in Mammalian Spermatocytes. Current biology : CB 30 30853435
2022 SCF ubiquitin E3 ligase regulates DNA double-strand breaks in early meiotic recombination. Nucleic acids research 24 35489071
2021 Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice. Nucleic acids research 24 33619545
2016 Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor. BMC cancer 20 27229929
2023 Characterization of the REC114-MEI4-IHO1 complex regulating meiotic DNA double-strand break formation. The EMBO journal 16 37431931
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 14 33842489
2024 Principles of chromosome organization for meiotic recombination. Molecular cell 13 38657614
2024 Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes. Nature communications 9 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
2025 Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids. Nature communications 2 40593736
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