Affinage

HORMAD2

HORMA domain-containing protein 2 · UniProt Q8N7B1

Length
307 aa
Mass
35.3 kDa
Annotated
2026-04-28
35 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HORMAD2 is a meiosis-specific HORMA domain protein that functions as a sensor of chromosome asynapsis, recruiting ATR kinase activity and BRCA1 to unsynapsed chromosome axes to activate a surveillance checkpoint that eliminates defective oocytes. HORMAD2 preferentially associates with unsynapsed axes throughout meiotic prophase, where it is positioned at the periphery of the SYCP3/SYCP2 axis core, and engages HORMAD1 through a conserved C-terminal closure motif–HORMA domain interaction analogous to the Mad2 safety-belt mechanism (PMID:25446517, PMID:37794593, PMID:31444302). HORMAD2-dependent ATR accumulation on unsynapsed axes drives asynapsis-specific oocyte elimination (distinct from the DNA damage checkpoint), while HORMAD2 also inhibits intersister recombination repair of spontaneous DSBs, linking persistent asynapsis to CHK2-dependent oocyte culling (PMID:22549958, PMID:23039116, PMID:28844861, PMID:39961811). Upon synapsis, the TRIP13 AAA-ATPase engages the N-terminal region of HORMAD2 to strip it from chromosome axes; failure of this removal—caused by TRIP13 loss or N-terminal perturbation—results in ectopic BRCA1 recruitment and unintended oocyte elimination, establishing TRIP13-dependent HORMAD2 removal as essential for female fertility (PMID:19851446, PMID:38401263, PMID:40050306).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2009 High

    Establishing that HORMAD2 preferentially marks unsynapsed chromosome axes and that TRIP13 is required for its depletion upon synapsis answered the foundational question of where HORMAD2 acts and how its distribution is regulated.

    Evidence Immunofluorescence in wild-type and multiple mutant mouse spermatocytes/oocytes (TRIP13-deficient, DSB-defective, SC-defective)

    PMID:19851446

    Open questions at the time
    • Mechanism by which TRIP13 removes HORMAD2 was unknown
    • Whether HORMAD2 has a functional role beyond a marker of unsynapsed axes was unresolved
    • Direct physical interaction between TRIP13 and HORMAD2 not demonstrated
  2. 2012 High

    Two independent knockout studies demonstrated that HORMAD2 is specifically required for ATR recruitment to unsynapsed axes (not DSB sites) and for asynapsis-specific oocyte elimination, separating the asynapsis surveillance pathway from the DNA damage checkpoint.

    Evidence Hormad2 knockout mice; epistasis with Spo11−/− and Dmc1−/− backgrounds; immunofluorescence for ATR, γH2AX, sex body markers; oocyte counting

    PMID:22549958 PMID:23039116

    Open questions at the time
    • Molecular mechanism by which HORMAD2 recruits ATR was unclear
    • Whether HORMAD2 acts directly or through HORMAD1 in checkpoint activation was unresolved
    • Role of HORMAD2 phosphorylation in ATR signaling not established
  3. 2012 Medium

    The finding that BRCA1 and SYCP3 are required for normal HORMAD1/2 phosphorylation connected HORMAD2 modification to the meiotic silencing of unsynapsed chromatin (MSUC) machinery, revealing upstream regulators of HORMAD2 phosphorylation.

    Evidence Phospho-specific immunofluorescence in Brca1, Sycp3, and recombination-initiation mutant mice

    PMID:22346761

    Open questions at the time
    • Identity of the kinase directly phosphorylating HORMAD2 was not determined
    • Functional consequences of reduced HORMAD2 phosphorylation on checkpoint activation not tested directly
    • Relationship between MSUC and asynapsis checkpoint was unclear
  4. 2014 Medium

    Biochemical and structural analysis revealed that HORMAD1 binds a C-terminal closure motif on HORMAD2 in a safety-belt mechanism conserved from worms to mammals, explaining the molecular basis of HORMAD2 recruitment to chromosome axes via HORMAD1.

    Evidence Biochemical pulldown and structural analysis of C. elegans HORMA proteins with validation of the conserved HORMAD1–HORMAD2 peptide interaction in mammals

    PMID:25446517

    Open questions at the time
    • Mammalian interaction was inferred partly from C. elegans structural data
    • Whether disrupting this interaction in vivo affects HORMAD2 axis localization was untested
    • Stoichiometry and dynamics of the HORMAD1–HORMAD2 complex on axes were unknown
  5. 2017 High

    Epistasis experiments showed that HORMAD2 deletion rescues fertility of Trip13-mutant oocytes and that persistent HORMAD1/2 on synapsed axes inhibits intersister DSB repair, positioning HORMAD2 as a functional effector—not merely a marker—of the asynapsis checkpoint and recombination control.

    Evidence Hormad2 deletion in Trip13 mutant mice; oocyte survival analysis; DSB marker quantification

    PMID:28844861

    Open questions at the time
    • Mechanism by which HORMAD2 inhibits intersister recombination was not defined
    • Whether HORMAD2 acts through ATR or through a distinct effector for recombination control was unresolved
  6. 2019 High

    Super-resolution imaging placed HORMAD2 at the periphery of the meiotic chromosome axis core, resolving its nanoscale position relative to SYCP3/SYCP2 and cohesins.

    Evidence Expansion STORM (ExSTORM) super-resolution microscopy at 10–20 nm resolution in mouse spermatocytes

    PMID:31444302

    Open questions at the time
    • How peripheral localization relates to HORMAD2 function in ATR recruitment was not addressed
    • Whether HORMAD2 contacts the central element of the SC prior to removal was unknown
  7. 2020 Medium

    Pathogenic TRIP13 variants cause HORMAD2 accumulation in human cells, confirming that the TRIP13–HORMAD2 regulatory axis is conserved beyond mouse and operates in somatic cells.

    Evidence Expression of TRIP13 variants in HeLa cells; immunoblotting for HORMAD2 in patient-derived lymphoblastoid cells

    PMID:32473092

    Open questions at the time
    • Functional consequence of HORMAD2 accumulation in somatic cells not characterized
    • Whether TRIP13 directly contacts HORMAD2 or acts via HORMAD1 was still unclear
  8. 2022 Medium

    RAD1 (9-1-1 complex subunit) was shown to be required for HORMAD2 phosphorylation as an ATR target, identifying the upstream DNA damage sensor complex that channels ATR activity toward HORMAD2.

    Evidence Testis-specific Rad1 conditional knockout mice; immunofluorescence for phospho-HORMAD2 on meiotic chromosome spreads

    PMID:35133274

    Open questions at the time
    • Whether 9-1-1 recruits ATR to HORMAD2 directly or through an intermediate was not resolved
    • Specific phosphorylation sites on HORMAD2 were not mapped
  9. 2023 High

    Crystal structure of human HORMAD1 bound to a HORMAD2-derived closure motif peptide (sharing a conserved Ser-Glu-Pro sequence) defined the atomic interface and linked the HORMAD1–HORMAD2 interaction to homologous recombination and mismatch repair functions.

    Evidence X-ray crystallography of human HORMAD1; biochemical binding assays with HORMAD2 peptides; mutagenesis; cell-based HR and MMR reporter assays

    PMID:37794593

    Open questions at the time
    • In vivo meiotic consequence of disrupting the specific binding interface was not tested
    • Whether HORMAD2 plays a direct role in somatic HR/MMR or acts only through HORMAD1 was unclear
  10. 2024 High

    Knockin mouse studies demonstrated that the N-terminal region of HORMAD2 is critical for TRIP13-mediated removal from synapsed axes: N-terminal tagging caused ectopic HORMAD2 persistence on synapsed regions and relocalization to the SC central region, and identified HORMAD1 and SYCP2 as HORMAD2-associated proteins by co-IP/MS.

    Evidence N-terminal 3×FLAG-HA tagging knockin mouse; co-immunoprecipitation with mass spectrometry; super-resolution microscopy; sperm count analysis

    PMID:38401263

    Open questions at the time
    • Whether TRIP13 directly engages the HORMAD2 N-terminus or acts through an adaptor (e.g., p31comet) was not resolved
    • How ectopic HORMAD2 relocates to the central region of the SC was mechanistically unclear
  11. 2025 High

    Retained HORMAD1/2 on synapsed axes (via TRIP13 depletion) recruit BRCA1 to trigger the asynapsis checkpoint and oocyte elimination; HORMAD1 binds BRCA1 via a HORMA domain interface near its N-terminus, while HORMAD2 contributes to BRCA1 recruitment. N-terminal tagging of either HORMAD blocks BRCA1 recruitment and oocyte elimination, explaining why tagged HORMAD2 persistence is not toxic.

    Evidence Co-immunoprecipitation; TRIP13-depletion and N-terminal tagging knockin mice; oocyte elimination assays; HORMAD1 mutagenesis

    PMID:40050306

    Open questions at the time
    • Direct versus indirect contribution of HORMAD2 to BRCA1 recruitment not fully separated from HORMAD1
    • Structural basis of the HORMAD1–BRCA1 interface not determined
    • Whether HORMAD2 contacts additional checkpoint effectors beyond BRCA1 and ATR is unknown
  12. 2025 Medium

    Double-mutant analysis confirmed that HORMAD2 is specifically required for asynapsis-induced (Spo11-dependent) but not DNA damage-induced (Dmc1-dependent) oocyte apoptosis, reinforcing the pathway specificity first observed in 2012.

    Evidence Hormad2/Spo11 and Hormad2/Dmc1 double-mutant mice; immunohistochemical apoptosis assay on perinatal ovaries

    PMID:39961811

    Open questions at the time
    • Molecular distinction between asynapsis and DNA damage checkpoint signaling downstream of HORMAD2 not fully elucidated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: whether TRIP13 directly engages the HORMAD2 N-terminus or acts through an adaptor such as p31comet; the identity and functional significance of specific HORMAD2 phosphorylation sites; and whether HORMAD2 has checkpoint effector functions independent of HORMAD1.
  • Direct TRIP13–HORMAD2 physical interaction and structural basis not demonstrated
  • Specific phosphorylation sites on HORMAD2 and their individual contributions to ATR signaling not mapped
  • Whether HORMAD2 has HORMAD1-independent roles in meiotic surveillance or recombination control remains untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005694 chromosome 5 GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-73894 DNA Repair 2
Partners
ATRBRCA1HORMAD1RAD1SYCP2TRIP13

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Mouse HORMAD2 preferentially associates with unsynapsed chromosome axes throughout meiotic prophase and is depleted from synapsed axes. TRIP13 AAA-ATPase is required for the reciprocal distribution of HORMADs and SYCP1/SC-components along chromosome axes, establishing that SC formation (directly or indirectly) promotes HORMAD depletion from synapsed axes. Immunofluorescence analysis of wild-type and mutant (TRIP13-deficient, DSB-defective, SC-defective) mouse spermatocytes and oocytes; genetic epistasis with multiple mutants PLoS genetics High 19851446
2012 HORMAD2 is required for the accumulation of the checkpoint kinase ATR along unsynapsed chromosome axes (but not at DSBs or DSB-associated chromatin loops), and this HORMAD2-dependent ATR recruitment constitutes a distinct asynapsis surveillance mechanism that eliminates asynaptic oocytes (Spo11−/− but not Dmc1−/− oocytes). Hormad2 knockout mouse generation; immunofluorescence for ATR on meiotic chromosomes; analysis of Spo11−/−, Dmc1−/−, and double-mutant oocyte survival Genes & development High 22549958
2012 HORMAD2 deficiency impairs proper recruitment of ATR activity to unsynapsed chromosomes in male mice, causing characteristic sex body malformation (ATR/γH2AX-enriched domain dissociated from elongated sex chromosome axes) and spermatocyte loss; in females, HORMAD2-dependent pseudo-sex body formation (local ATR concentration) drives elimination of Spo11-deficient asynaptic oocytes. Hormad2 knockout mouse; immunofluorescence for ATR, γH2AX, sex body markers; Hormad2/Spo11 double-mutant analysis with oocyte counting Genes to cells High 23039116
2012 HORMAD2 (along with HORMAD1) becomes phosphorylated during meiotic prophase I; BRCA1 and SYCP3 are required for normal phosphorylation levels of HORMAD1 and HORMAD2 (but not SMC3), and reduced HORMAD1/2 phosphorylation is associated with impaired targeting of the meiotic silencing of unsynapsed chromatin (MSUC) machinery. Immunofluorescence with phospho-specific antibodies; analysis of Brca1, Sycp3, and recombination-initiation mutant mice PLoS genetics Medium 22346761
2014 Mammalian HORMAD1 binds a peptide motif found at the C-terminus of HORMAD2, indicating that intermolecular HORMA domain–closure motif interactions (analogous to the Mad2 'safety belt') are a conserved feature of meiotic chromosome structure, and this interaction is relevant for HORMAD2 recruitment to chromosome axes. Biochemical pulldown and structural analysis of C. elegans HORMA proteins with validation of conserved HORMAD1–HORMAD2 C-terminal peptide interaction in mammals Developmental cell Medium 25446517
2017 HORMAD1/2 on unsynapsed chromosome axes inhibit repair of spontaneous DSBs via intersister recombination; CHK2-dependent DNA damage checkpoint culls oocytes that accumulate ~10 spontaneous DSBs in late prophase I. Hormad2 deletion rescued fertility of Trip13 mutant oocytes (which retain HORMADs on synapsed chromosomes), establishing that HORMAD2 promotes intersister repair inhibition and DSB-dependent oocyte elimination downstream of asynapsis. Hormad2 deletion in Trip13 mutant mice; genetic epistasis; analysis of oocyte survival and DSB markers Molecular cell High 28844861
2019 By expansion STORM super-resolution microscopy of mouse spermatocytes, HORMAD2 is localized to the periphery of the chromosome axis core (which is formed by SYCP3 filaments), arrayed around the SYCP3/SYCP2 C-terminal core together with cohesin complexes and the N-terminus of SYCP2. Expansion microscopy coupled with 2-color STORM (ExSTORM) imaging at 10–20 nm resolution in mouse spermatocytes Proceedings of the National Academy of Sciences of the United States of America High 31444302
2020 Pathogenic missense variants in TRIP13 reduce its protein abundance and cause accumulation of HORMAD2 (its downstream molecule) in HeLa cells and proband-derived lymphoblastoid cells, confirming that TRIP13 AAA-ATPase activity is required for HORMAD2 turnover/removal in human cells. In vitro expression of TRIP13 variants in HeLa cells; immunoblotting for HORMAD2 levels; analysis of patient-derived lymphoblastoid cells American journal of human genetics Medium 32473092
2022 RAD1 (shared subunit of all 9-1-1 complexes) is required for phosphorylation of HORMAD2 (as an ATR target) on meiotic chromosomes; testis-specific Rad1 disruption caused severe synapsis defects and impaired ATR signaling including HORMAD2 phosphorylation, unlike disruption of only the canonical HUS1 or RAD9A subunits. Testis-specific Rad1 knockout mice; immunofluorescence for phospho-HORMAD2 and other ATR targets on meiotic chromosome spreads; comparison with Hus1 and Rad9a knockouts eLife Medium 35133274
2023 The HORMA domain of HORMAD1 binds a peptide motif from HORMAD2 (sharing a conserved Ser-Glu-Pro sequence with HORMAD1's own closure motif and MCM9), in a self-closed intra-molecular interaction mode; structural comparison and cell-based assays show this HORMA–closure motif interaction contributes to DNA mismatch repair and HR repair. Crystal structure of human HORMAD1; biochemical binding assays with HORMAD2-derived peptides; mutagenesis; cell-based HR and MMR reporter assays Structure High 37794593
2024 The N-terminal region of HORMAD2 is critical for its timely removal from synapsed meiotic chromosome axes by TRIP13; N-terminal 3×FLAG-HA tagging causes HORMAD2 to persist ectopically on synapsed regions in pachynema and localizes to the central region of the synaptonemal complex rather than lateral elements, while HORMAD1 remains on lateral elements. Co-immunoprecipitation with mass spectrometry identified HORMAD1 and SYCP2 as HORMAD2-associated proteins in testis. N-terminal tagging knockin mouse; co-immunoprecipitation coupled with mass spectrometry; super-resolution microscopy; sperm count analysis Reproduction High 38401263
2025 When HORMAD1 and HORMAD2 are retained on synapsed chromosome axes (by TRIP13 depletion), they recruit BRCA1 and activate the chromosome asynapsis checkpoint triggering oocyte elimination. HORMAD1 co-immunoprecipitates with BRCA1 via an interface on its HORMA domain near the N-terminus (not through the canonical closure motif-binding mode); HORMAD2 co-immunoprecipitates weakly with BRCA1 but also contributes to its recruitment. N-terminal tagging of HORMAD1 or HORMAD2 retains them on synapsed axes without triggering oocyte elimination due to defective BRCA1 recruitment. Co-immunoprecipitation; TRIP13-depletion mouse model; N-terminal tagging knockin mice; oocyte elimination assays; mutagenesis of HORMAD1 interaction interface Nature communications High 40050306
2025 Asynapsis-induced oocyte apoptosis (in Spo11-deficient mice) but not DNA damage-induced apoptosis (in Dmc1-deficient mice) is significantly dependent on HORMAD2, confirming a specific role for HORMAD2 in the asynapsis surveillance pathway distinct from the DNA damage checkpoint. Double-mutant analysis (Hormad2/Spo11 and Hormad2/Dmc1) with immunohistochemical apoptosis assay on perinatal mouse ovaries using squash method Histochemistry and cell biology Medium 39961811

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS genetics 327 19851446
2012 Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms. Genes & development 121 22549958
2012 Pathogenesis of immunoglobulin A nephropathy: recent insight from genetic studies. Annual review of medicine 107 23072577
2014 The chromosome axis controls meiotic events through a hierarchical assembly of HORMA domain proteins. Developmental cell 103 25446517
2020 Bi-allelic Missense Pathogenic Variants in TRIP13 Cause Female Infertility Characterized by Oocyte Maturation Arrest. American journal of human genetics 99 32473092
2017 The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure. Molecular cell 97 28844861
2019 Molecular organization of mammalian meiotic chromosome axis revealed by expansion STORM microscopy. Proceedings of the National Academy of Sciences of the United States of America 82 31444302
2012 HORMAD2 is essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity. Genes to cells : devoted to molecular & cellular mechanisms 63 23039116
2012 Phosphorylation of chromosome core components may serve as axis marks for the status of chromosomal events during mammalian meiosis. PLoS genetics 62 22346761
2018 The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells. Scientific reports 47 30333500
2015 MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. Proceedings of the National Academy of Sciences of the United States of America 44 26240347
2020 Dynamic Shifts in the HIV Proviral Landscape During Long Term Combination Antiretroviral Therapy: Implications for Persistence and Control of HIV Infections. Viruses 36 31991737
2020 State changes of the HORMA protein ASY1 are mediated by an interplay between its closure motif and PCH2. Nucleic acids research 34 32558910
2019 Identification of susceptibility locus shared by IgA nephropathy and inflammatory bowel disease in a Chinese Han population. Journal of human genetics 28 31857673
2016 Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy. Journal of medical genetics 28 27941131
2012 HORMAD2/CT46.2, a novel cancer/testis gene, is ectopically expressed in lung cancer tissues. Molecular human reproduction 28 22893617
2020 Prdm9 Intersubspecific Interactions in Hybrid Male Sterility of House Mouse. Molecular biology and evolution 23 32642764
2023 MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy. Kidney international 16 37414396
2016 SOHLH2 is essential for synaptonemal complex formation during spermatogenesis in early postnatal mouse testes. Scientific reports 13 26869299
2021 Genome-wide DNA methylation and RNA expression differences correlate with invasiveness in melanoma cell lines. Epigenomics 12 33781093
2024 WGCNA combined with machine learning to explore potential biomarkers and treatment strategies for acute liver failure, with experimental validation. iLIVER 8 40635857
2022 Multiple 9-1-1 complexes promote homolog synapsis, DSB repair, and ATR signaling during mammalian meiosis. eLife 8 35133274
2023 Structural and biochemical insights into the interaction mechanism underlying HORMAD1 and its partner proteins. Structure (London, England : 1993) 7 37794593
2022 Genic and chromosomal components of Prdm9-driven hybrid male sterility in mice (Mus musculus). Genetics 7 35924978
2015 A rare Robertsonian translocation rob(14;22) carrier with azoospermia, meiotic defects, and testicular sperm aneuploidy. Systems biology in reproductive medicine 6 26043179
2017 A strategy to apply quantitative epistasis analysis on developmental traits. BMC genetics 5 28506208
2014 Dosage compensation of an aneuploid genome in mouse spermatogenic cells. Biology of reproduction 5 24790161
2023 Mucosal Immune Defence Gene Polymorphisms as Relevant Players in the Pathogenesis of IgA Vasculitis? International journal of molecular sciences 4 37685869
2025 Genome-wide association study of pulpal and apical diseases. Nature communications 3 40701953
2024 A homozygous stop codon in HORMAD2 in a patient with recurrent digynic triploid miscarriage. Molecular genetics & genomic medicine 3 38400599
2025 Aberrant activation of chromosome asynapsis checkpoint triggers oocyte elimination. Nature communications 2 40050306
2022 Prdm9 deficiency of rat oocytes causes synapsis among non-homologous chromosomes and aneuploidy. Mammalian genome : official journal of the International Mammalian Genome Society 2 35596034
2025 A simple immunohistochemical method for perinatal mammalian ovaries revealed different kinetics of oocyte apoptosis caused by DNA damage and asynapsis. Histochemistry and cell biology 1 39961811
2024 The N-terminal modification of HORMAD2 causes its ectopic persistence on synapsed chromosomes without meiotic blockade. Reproduction (Cambridge, England) 1 38401263
2026 Aberrant signaling in tonsillar B cells producing pathogenic O-glycoforms of IgA1 in IgA nephropathy. Frontiers in immunology 0 41694356