| 2009 |
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-component along chromosome axes, indicating TRIP13 promotes HORMAD2 removal from synapsed chromatin. |
Immunofluorescence analysis of wild-type and mutant (TRIP13-deficient, DSB-processing mutant) mouse spermatocytes/oocytes; co-localization with SC markers |
PLoS genetics |
High |
19851446
|
| 2012 |
HORMAD2 is required for accumulation of the checkpoint kinase ATR along unsynapsed chromosome axes (but not at DNA DSBs or DSB-associated chromatin loops), and this HORMAD2-dependent ATR recruitment constitutes a distinct asynapsis surveillance mechanism; HORMAD2 knockout eliminates asynaptic Spo11−/− oocytes but not DSB-repair-defective Dmc1−/− oocytes, demonstrating that asynapsis surveillance and DSB surveillance are mechanistically distinct. |
Hormad2 knockout mouse generation; immunofluorescence for ATR on meiotic chromosomes; genetic epistasis using Spo11−/− and Dmc1−/− double mutants; oocyte counting |
Genes & development |
High |
22549958
|
| 2012 |
HORMAD2 deficiency impairs proper recruitment of ATR activity to unsynapsed chromosomes; in males, loss of HORMAD2 causes partial dissociation of the sex body (ATR- and γH2AX-enriched domain) from elongated sex chromosome axes leading to spermatocyte loss; in females, HORMAD2-dependent pseudo-sex body formation (likely via local ATR concentration) drives elimination of asynaptic Spo11-deficient oocytes. |
Hormad2 knockout mouse; immunofluorescence for ATR, γH2AX, SYCP1, SYCP3; Hormad2/Spo11 double-mutant analysis; oocyte counting in a gene-dosage series |
Genes to cells : devoted to molecular & cellular mechanisms |
High |
23039116
|
| 2012 |
HORMAD2 is post-translationally phosphorylated during meiotic prophase I; phosphorylation of HORMAD2 depends on BRCA1 and SYCP3 for normal levels, and is dramatically reduced in the absence of meiotic recombination initiation; reduced HORMAD2 phosphorylation is associated with impaired targeting of the MSUC (meiotic silencing of unsynapsed chromatin) machinery to unsynapsed chromosomes. |
Western blot and immunofluorescence with phospho-specific analysis; genetic requirement tested in Spo11, BRCA1, and SYCP3 mutant spermatocytes |
PLoS genetics |
Medium |
22346761
|
| 2014 |
Mammalian HORMAD1 binds a cognate peptide motif found at the C-terminus of HORMAD2, indicating that HORMAD2 is recruited to the chromosome axis via a 'safety-belt' HORMA domain–closure motif interaction conserved from C. elegans to mammals. |
Biochemical binding assays (pulldown); structural analysis of C. elegans orthologs; sequence analysis identifying conserved closure motif in HORMAD2 C-terminus |
Developmental cell |
Medium |
25446517
|
| 2017 |
HORMAD1/2 on unsynapsed chromosome axes inhibit repair of spontaneous DSBs by intersister recombination; when a threshold (~10) of late-prophase spontaneous DSBs accumulates on unsynapsed axes bearing HORMAD1/2, the CHK2-dependent DNA damage checkpoint is triggered to eliminate oocytes; Hormad2 deletion rescued fertility of Trip13-mutant females (which cannot remove HORMADs from synapsed chromosomes), establishing that HORMAD2 is epistatic to TRIP13 in this checkpoint pathway. |
Genetic epistasis: Hormad2 deletion in Trip13 hypomorphic females; oocyte counting; immunofluorescence for DSB markers; CHK2 pathway analysis |
Molecular cell |
High |
28844861
|
| 2019 |
Using expansion microscopy coupled with 2-color STORM (ExSTORM) at 10–20 nm resolution in mouse spermatocytes, HORMAD2 was shown to be arrayed around the SYCP3/SYCP2 C-terminus filament core of the meiotic chromosome axis, positioned peripherally relative to the compact axial core. |
Expansion microscopy + 2-color STORM (ExSTORM) super-resolution imaging of mouse spermatocytes |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
31444302
|
| 2020 |
TRIP13 pathogenic variants reduce TRIP13 protein abundance and cause HORMAD2 to accumulate (fail to be removed) in HeLa cells and patient-derived lymphoblastoid cells, establishing that TRIP13 enzymatic activity is required for HORMAD2 disassembly in a human cellular context. |
In vitro cell assays (HeLa overexpression); patient-derived lymphoblastoid cells; western blot for HORMAD2 levels |
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 during meiosis; testis-specific Rad1 disruption impaired HORMAD2 phosphorylation along with other ATR targets (H2AX, CHK1), placing 9-1-1 complexes upstream of ATR-mediated HORMAD2 modification. |
Testis-specific Rad1 knockout mice; immunofluorescence and western blot for phospho-HORMAD2 and other ATR targets on meiotic chromosomes |
eLife |
Medium |
35133274
|
| 2022 |
In Prdm9-deficient rat oocytes, non-homologous synapsis (NHS) is accompanied by HORMAD2 levels similar to those on pachytene chromosomes with homologous synapsis; this indicates that NHS bypasses the HORMAD2-based asynapsis signal and allows oocytes to evade meiotic checkpoints, linking HORMAD2 checkpoint evasion to subsequent aneuploidy. |
Immunofluorescence for HORMAD2 on rat oocyte chromosome spreads; comparison between homologous-synapsed and non-homologously-synapsed pachytene chromosomes in Prdm9-deficient animals |
Mammalian genome |
Medium |
35596034
|
| 2023 |
The crystal structure of human HORMAD1 reveals a self-closed conformation via intramolecular HORMA domain–closure motif interaction; structural and biochemical data show that a peptide from HORMAD2 binds HORMAD1 in the same mode as HORMAD1's own closure motif, with both sharing a conserved Ser-Glu-Pro sequence; this HORMAD1–HORMAD2 interaction contributes to HORMAD1-dependent homologous recombination repair in cell-based assays. |
X-ray crystallography of human HORMAD1; peptide-binding biochemical assays; cell-based HR repair reporter assays |
Structure (London, England : 1993) |
High |
37794593
|
| 2024 |
N-terminal tagging (3×FLAG-HA) of HORMAD2 prevents its timely removal from synapsed chromosome axes by TRIP13; co-immunoprecipitation coupled with mass spectrometry identified HORMAD1 and SYCP2 as HORMAD2-associated proteins in the testis; super-resolution microscopy showed that N-terminally tagged HORMAD2 redistributes to the central region of the synaptonemal complex rather than the lateral elements, without blocking meiosis but reducing sperm count in males. |
N-terminal knock-in tagging in mice; co-IP + mass spectrometry; super-resolution microscopy; fertility and sperm count assays |
Reproduction (Cambridge, England) |
High |
38401263
|
| 2025 |
When HORMAD1 and HORMAD2 are retained on synapsed chromosome axes (in TRIP13-deficient contexts), they recruit BRCA1 and activate the chromosome asynapsis checkpoint, triggering oocyte elimination; mechanistically, HORMAD1 co-immunoprecipitates with BRCA1 via an interface on its HORMA domain near the N-terminus (not through the canonical closure-motif binding mode), while HORMAD2 co-immunoprecipitates with BRCA1 weakly but also contributes to BRCA1 recruitment; N-terminal tagging of HORMAD1/2 retains them on synapsed axes but abolishes BRCA1 recruitment and oocyte elimination, confirming the N-terminal interface is required. |
Co-immunoprecipitation; N-terminal-tagged HORMAD knock-in mice; immunofluorescence for BRCA1 on meiotic chromosomes; oocyte counting in multiple genetic backgrounds |
Nature communications |
High |
40050306
|
| 2025 |
Using a squash immunohistochemical method for perinatal mouse ovaries, asynapsis-induced oocyte apoptosis (but not DNA damage-induced apoptosis) was shown to be significantly dependent on HORMAD2 in double-mutant analysis, confirming HORMAD2's specific role in the asynapsis surveillance pathway distinct from the DNA damage checkpoint. |
Squash immunohistochemistry; double-mutant analysis (Hormad2 × Spo11 and Hormad2 × Dmc1); apoptosis kinetics measurement in perinatal ovaries |
Histochemistry and cell biology |
Medium |
39961811
|