Affinage

MEI4

Meiosis-specific protein MEI4 · UniProt A8MW99

Length
385 aa
Mass
44.0 kDa
Annotated
2026-06-10
22 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MEI4 is a conserved component of the meiotic recombination machinery that promotes SPO11/Spo11-mediated DNA double-strand break (DSB) formation, acting genetically upstream of strand-exchange and repair factors such as RAD52 (PMID:2693205, PMID:20551173). MEI4 functions as the core of a stable, conserved complex with REC114 and the Mer2 ortholog IHO1, in which two REC114 C-terminal dimers cup an N-terminal MEI4 α-helix to form a 2:1 REC114:MEI4 heterotrimer that can further oligomerize (PMID:30569039, PMID:37442580, PMID:37431931). This minimal REC114–MEI4 unit binds DNA cooperatively through two oppositely oriented DNA-binding sites and drives DNA-dependent condensate formation, bridging and condensing multiple DNA duplexes — the biophysical basis for assembling the DSB machinery (PMID:37442580, PMID:37442581). MEI4 concentrates in discrete foci on meiotic chromosome axes distinct from downstream recombination markers, and its axis loading depends on the chromosome-axis factor HORMAD1 together with the cohesins REC8/RAD21L, with axis-associated MEI4 levels quantitatively limiting DSB formation (PMID:20551173, PMID:25795304). MEI4's DNA-binding activity, residing in its N-terminal region, and the C-terminal segment that stabilizes the MEI4–REC114 subcomplex on axes are both required for fertility: bi-allelic and truncating MEI4 variants impair DNA binding or axis stabilization and cause oogenesis defects and premature ovarian insufficiency, modeled in knock-in mice (PMID:38252283, PMID:41419020). In the fission yeast and budding yeast lineages, the Mei4 ortholog has an additional, distinct role as a forkhead/HNF3 transcription factor that binds the FLEX cis-element to activate middle-meiotic genes and autoregulate its own expression, coordinating recombination timing with premeiotic DNA replication (PMID:9528784, PMID:10747048, PMID:16286472).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1989 Medium

    Established where MEI4 acts in meiotic recombination, placing it upstream of the strand-exchange/repair machinery rather than within it.

    Evidence Genetic epistasis with spo13 suppression in S. cerevisiae mei4 spo13 rad52 triple mutants

    PMID:2693205

    Open questions at the time
    • Did not define a molecular activity for MEI4
    • No protein partners identified
    • Mechanism of DSB promotion unknown
  2. 1992 Medium

    Defined MEI4 as a meiosis-specific gene whose product is required for synaptonemal complex formation, linking it to chromosome morphogenesis.

    Evidence Sequencing, Northern blot, and cytology of meiotic chromosomes in S. cerevisiae mei4 deletion strains

    PMID:1545815

    Open questions at the time
    • Whether synapsis failure is a direct consequence of failed DSB formation not resolved
    • No biochemical activity assigned
  3. 1998 High

    Revealed that the S. pombe Mei4 ortholog is a sequence-specific forkhead transcription factor, defining a transcriptional function distinct from the DSB role in budding yeast/mouse.

    Evidence Complementation cloning, gel-shift with recombinant forkhead domain, one-hybrid and promoter deletion in S. pombe

    PMID:9528784

    Open questions at the time
    • Full target-gene repertoire not yet mapped
    • Relationship between fission-yeast transcriptional role and DSB-machinery role of orthologs unaddressed
  4. 2000 High

    Identified the FLEX cis-element as the genomic recognition site through which S. pombe Mei4 activates middle-meiotic genes and autoregulates itself, building the transcriptional regulatory logic.

    Evidence Genome-wide promoter scanning, Northern blots, forkhead-FLEX binding, and reporter assays in S. pombe

    PMID:10747048

    Open questions at the time
    • Co-factors required for activation not yet identified
    • How FLEX targets are selected genome-wide unclear
  5. 2005 Medium

    Showed that mei4+ transcription is gated by the replication checkpoint, coupling onset of meiotic recombination to completion of premeiotic DNA replication.

    Evidence Hydroxyurea replication block with rad3/cds1/chk1/mek1 mutants and Northern blot in S. pombe

    PMID:16286472

    Open questions at the time
    • Direct checkpoint target within the mei4 promoter not defined
    • Applies to the transcriptional role; checkpoint control of the metazoan DSB role separate
  6. 2006 High

    Defined the Mei4–Rec114–Mer2 complex as a discrete physical and cytological entity required for DSB formation, distinct from the Mre11/Rec102 machinery.

    Evidence Co-immunoprecipitation and cytological co-localization on meiotic chromosomes in S. cerevisiae

    PMID:16783010

    Open questions at the time
    • Stoichiometry and direct binding interfaces not resolved
    • Biochemical activity of the complex unknown
  7. 2007 Medium

    Mapped the interaction hierarchy showing Mei4 axis localization depends on Rec114/Mer2 and connecting the subcomplex to Spo11 via Rec102.

    Evidence Two-hybrid, deletion mapping, and cytological localization in deletion backgrounds in S. cerevisiae

    PMID:17558514

    Open questions at the time
    • Direct vs indirect nature of Mei4-Spo11 link not established
    • Interaction regions not resolved structurally
  8. 2010 High

    Demonstrated functional conservation of MEI4 to mammals, showing it is essential for DSB formation, localizes to axis foci, and directly binds REC114 via conserved motifs.

    Evidence Mei4-/- mouse phenotyping, immunofluorescence, and pulldown/co-IP with motif mutagenesis

    PMID:20551173

    Open questions at the time
    • Complex stoichiometry and structure not yet defined
    • How axis foci promote SPO11 cleavage unknown
  9. 2011 Medium

    Showed the S. pombe DSB-pathway ortholog Rec24 is required genome-wide for crossing-over and is stabilized on linear elements by Rec7, separating axis loading from Spo11 activity.

    Evidence Gene disruption, cytological localization, and co-IP in S. pombe

    PMID:21429938

    Open questions at the time
    • Molecular basis of linear-element recruitment unresolved
    • Direct DNA-binding not tested here
  10. 2011 Medium

    Extended the fission-yeast transcription-factor role to meiotic chromosome dynamics, showing forkhead-domain-dependent control of telomere dispersal at meiosis I.

    Evidence Deletion and temperature-sensitive forkhead-domain point mutant with live-cell telomere imaging in S. pombe

    PMID:21449049

    Open questions at the time
    • Direct transcriptional targets driving telomere dispersal not identified
  11. 2014 Medium

    Linked Mei4 transcriptional output to timing of meiotic nuclear movements under checkpoint control, reinforcing replication-coupled regulation of meiotic progression.

    Evidence Deletion/overproduction with live-cell imaging and checkpoint-mutant analysis in S. pombe

    PMID:25492408

    Open questions at the time
    • Effector genes mediating nuclear-movement termination not defined
  12. 2015 High

    Identified the chromosome-axis determinants of MEI4 localization and established that axis-bound MEI4 is a quantitative limiting factor for DSB formation.

    Evidence HORMAD1, MEI1, REC8, RAD21L knockout mice with quantitative immunofluorescence of MEI4 and DSB markers

    PMID:25795304

    Open questions at the time
    • Direct vs indirect dependence of MEI4 on each axis factor not dissected
    • Mechanism converting axis loading into cleavage unknown
  13. 2018 High

    Resolved the mammalian REC114–MEI4–IHO1 complex biochemically and structurally, reconstituting the REC114-CTD:MEI4-NTD interaction and solving the REC114 N-terminal PH-like domain.

    Evidence REC114 KO mouse, co-IP from spermatocytes, in vitro domain reconstitution, X-ray crystallography

    PMID:30569039

    Open questions at the time
    • Complex stoichiometry not yet quantified
    • DNA-binding/condensation activity not yet characterized
  14. 2023 High

    Defined the molecular architecture and biochemical activity of the complex: a 2:1 REC114:MEI4 heterotrimer with opposed DNA-binding sites that drives cooperative DNA binding and condensation, providing the physical mechanism for DSB-machinery assembly.

    Evidence NMR/SAXS, AlphaFold2 modeling, in vitro reconstitution, single-molecule DNA condensation, and mutagenesis (S. cerevisiae and conserved models)

    PMID:37442580 PMID:37442581

    Open questions at the time
    • How condensates direct SPO11 to specific sites not resolved
    • In vivo relevance of condensation vs other functions
  15. 2023 High

    Established REC114 as a regulatory platform: the same PH-domain surface mediates mutually exclusive interactions with IHO1, TOPOVIBL, and ANKRD31, organizing the higher-order DSB machinery around the MEI4 heterotrimer.

    Evidence AlphaFold2 modeling with SEC, native MS, co-IP, and mutagenesis in the mouse system

    PMID:37431931

    Open questions at the time
    • Temporal ordering of competing interactions in vivo unknown
    • Functional consequence of heterotrimer dimerization not defined
  16. 2024 Medium

    Connected MEI4 to human disease by showing N-terminal variants reduce DNA binding and cause oogenesis defects, establishing DNA-binding activity as required for reproductive function.

    Evidence In vitro DNA interaction assays with variant proteins and a knock-in mouse model with oogenesis phenotyping

    PMID:38252283

    Open questions at the time
    • Single lab; allelic spectrum in patients limited
    • Whether variants affect condensation as well as binding not tested
  17. 2025 Medium

    Showed the MEI4 C-terminus stabilizes the MEI4–REC114 subcomplex on axes and that its truncation causes severe DSB defects, oocyte apoptosis via the HORMAD1-dependent synapsis checkpoint, and premature ovarian insufficiency, with haploinsufficiency.

    Evidence POI exome sequencing, in vitro DSB assay, Mei4Arg356* knock-in mouse with cytology and embryonic-development analysis

    PMID:41419020

    Open questions at the time
    • Structural basis of C-terminal axis stabilization not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the RMM condensate is converted into site-specific SPO11 cleavage — i.e. how DNA condensation and axis tethering are mechanistically coupled to catalytic DSB formation — remains unresolved.
  • No reconstitution of SPO11 cleavage from the RMM complex
  • Mechanism coupling condensation to catalysis unknown
  • Mre11 recruitment via Mer2 only shown in a preprint (idx 20)

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
CUF2HORMAD1IHO1MER2REC102REC114REC7
Complex memberships
REC114-MEI4-Mer2/IHO1 (RMM) complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 MEI4 in S. cerevisiae is required for meiotic DNA double-strand break formation and acts upstream of RAD52 in the meiotic recombination pathway, as established by genetic epistasis: mei4 spo13 rad52 mutants produce viable spores, placing MEI4 before RAD52. Genetic epistasis analysis (double/triple mutant analysis, spo13 suppression assay) Genetics Medium 2693205
1992 S. cerevisiae MEI4 encodes a 450-amino-acid protein with meiosis-specific transcription; mei4 mutants form long axial elements but fail to undergo chromosome synapsis, establishing MEI4 as required for synaptonemal complex formation. DNA sequencing, cytological analysis of meiotic chromosomes in mei4 deletion strains, Northern blot Molecular and cellular biology Medium 1545815
1998 S. pombe mei4+ encodes a meiosis-specific transcription factor with an N-terminal forkhead/HNF3 DNA-binding domain that binds a GTAAAYA consensus sequence in the spo6+ promoter; a C-terminal 140-amino-acid region acts as a transcriptional activation domain. Functional complementation cloning, gel mobility shift assay (GST-Mei4 forkhead domain fusion), one-hybrid assay, promoter deletion analysis Molecular and cellular biology High 9528784
2000 S. pombe Mei4 binds a cis-acting element called FLEX in the promoter of its own gene and of multiple meiotic target genes (mde1–mde9), and mei4 transcription is positively autoregulated. Genome-wide promoter scanning, Northern blotting, forkhead-domain binding to FLEX element, reporter gene assay with ectopic Mei4 overproduction Genetics High 10747048
2006 S. cerevisiae Mei4, Rec114, and Mer2 form a distinct protein complex required for meiotic DSB formation; all three proteins co-immunoprecipitate and co-localize in foci on meiotic chromosomes, partially overlapping each other but distinct from Mre11 and Rec102 foci. Co-immunoprecipitation, cytological co-localization (fluorescence microscopy) on meiotic chromosomes Genetics High 16783010
2005 In S. pombe, the Rad3-Cds1 checkpoint pathway suppresses mei4+ transcription when premeiotic DNA replication is blocked, thereby coupling initiation of meiotic recombination (DSB formation) with DNA replication completion. Hydroxyurea block of replication, analysis in rad3, cds1, chk1, mek1 deletion mutants, Northern blot of mei4+ mRNA The Journal of biological chemistry Medium 16286472
2007 In S. cerevisiae, Mei4 chromosome localization is strongly dependent on Rec114 and Mer2; systematic two-hybrid and deletion analyses identified protein regions required for Mei4–Rec114 interaction; Rec102 N-terminal sequences mediate interactions with Rec114 and Mei4, connecting the Mei4-Rec114-Mer2 subgroup to Spo11. Two-hybrid analysis, deletion mapping, cytological localization in various deletion backgrounds Chromosoma Medium 17558514
2010 Mouse MEI4 is functionally conserved for meiotic DSB formation: Mei4−/− mice are deficient in meiotic DSBs, MEI4 localizes to discrete foci on meiotic chromosome axes (not overlapping DMC1 or RPA foci), and mouse MEI4 and REC114 interact directly with conserved motifs required for this interaction. Knockout mouse analysis, cytological localization (immunofluorescence), direct protein interaction assay (pulldown/co-IP), mutational analysis of conserved motifs Genes & development High 20551173
2011 S. pombe Rec24 (ortholog of mouse Mei4) is required genome-wide for crossing-over, localizes to linear elements on meiotic chromosomes in a Rec12 (Spo11)-independent manner, and forms complexes in vivo with Rec7; Rec7 is required for stabilization of Rec24 on linear elements. Gene disruption analysis, cytological localization, co-immunoprecipitation Journal of cell science Medium 21429938
2011 S. pombe Mei4 (forkhead transcription factor) is required for telomere dispersal from the spindle pole body at meiosis I onset; mei4Δ cells arrest with clustered telomeres, and a temperature-sensitive mei4-N136A allele in the forkhead DNA-binding domain shows the same phenotype reversibly. Gene deletion, temperature-sensitive point mutant in forkhead domain, live-cell imaging of telomere position Yeast (Chichester, England) Medium 21449049
2014 In S. pombe, Mei4 (transcription factor) controls termination of meiotic nuclear movements; loss of Mei4 prolongs nuclear movements, while Mei4 overproduction accelerates their termination; the Cds1 replication checkpoint represses mei4+ expression to link DNA replication to nuclear movement timing. Gene deletion/overproduction experiments, live-cell imaging of nuclear movement duration, checkpoint mutant analysis Genes to cells Medium 25492408
2015 Mouse HORMAD1 (a chromosome axis component) is required for MEI4 localization on meiotic chromosome axes; MEI1, REC8, and RAD21L also contribute to proper MEI4 localization; quantitative correlation between axis-associated MEI4 levels and DSB formation suggests MEI4 is a limiting factor for DSB formation. Knockout mouse analyses (HORMAD1 KO, MEI1 KO, REC8 KO, RAD21L KO), immunofluorescence cytology, quantitative analysis of MEI4 foci and DSB markers Journal of cell science High 25795304
2016 S. pombe Cuf2 is a transcriptional co-regulator that physically interacts with Mei4 in the nucleus; Cuf2 requires Mei4 for its function, and Cuf2 chromatin occupancy at target gene promoters depends on FLEX-like elements bound by Mei4. Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), chromatin immunoprecipitation (ChIP), promoter deletion analysis PloS one Medium 26986212
2018 Mouse REC114 is essential for meiotic DSB formation and forms a stable complex with MEI4 and IHO1 (Mer2 ortholog) in spermatocytes; in vitro reconstitution showed a stable complex between the REC114 C-terminal domain and the MEI4 N-terminal domain; the REC114 N-terminal domain has a structure similar to Pleckstrin homology (PH) domains. Mouse knockout analysis, co-immunoprecipitation from spermatocytes, in vitro reconstitution of REC114–MEI4 domain complex, X-ray crystallography of REC114 N-terminal domain Life science alliance High 30569039
2020 In S. cerevisiae, PAF1C histone modification complex components (Rtf1, Cdc73) show synthetic DSB formation defects when combined with tagged (but not untagged) alleles of REC114 or MER2, and SET1 deletion similarly affects tagged REC114 in a manner independent of SPP1, suggesting histone modification machinery influences the Rec114-Mer2-Mei4 complex in DSB formation. Genetic analysis, meiotic DSB assay in double mutants International journal of molecular sciences Low 32290544
2023 The S. cerevisiae Rec114–Mei4 complex forms a 2:1 heterotrimer (two Rec114 : one Mei4) in which Rec114 C-terminal dimers cup an N-terminal Mei4 α-helix; this minimal complex binds DNA cooperatively and forms large condensates; single-molecule experiments show the complex bridges multiple DNA duplexes and can condense DNA through long-range interactions. AlphaFold2 structural models are conserved across eukaryotes. NMR spectroscopy, AlphaFold2 structural modeling, in vitro reconstitution of heterotrimeric complex, single-molecule DNA condensation assay, mutagenesis Genes & development High 37442580
2023 AlphaFold2 modeling supported by NMR and SAXS shows that Rec114–Mei4 forms a 2:1 heterotrimer where Rec114 C-terminal dimers form α-helical chains that cup the N-terminal Mei4 α-helix; the interaction domain contains two DNA-binding sites pointing in opposite directions driving DNA-dependent condensation; Mer2 forms a parallel homotetrameric coiled coil that bridges coaligned DNA duplexes; both structures are conserved across eukaryotes though DNA-binding properties vary. AlphaFold2 modeling, NMR spectroscopy, SAXS, mutagenesis, in vitro DNA condensation assay Genes & development High 37442581
2023 Mouse REC114 forms homodimers and associates with MEI4 as a 2:1 REC114:MEI4 heterotrimer that further dimerizes; IHO1 forms coiled-coil-based tetramers; IHO1 directly interacts with the PH domain of REC114 via the same surface recognized by TOPOVIBL and ANKRD31, suggesting REC114 acts as a regulatory platform for mutually exclusive interactions. AlphaFold2 modeling, biochemical characterization (SEC, native MS), co-IP, mutagenesis The EMBO journal High 37431931
2024 Bi-allelic missense variants in human MEI4 (in the N-terminal region, amino acids 98–305) reduce MEI4–DNA interaction in vitro, and a knock-in mouse model with one variant causes female infertility with oogenesis developmental defects, demonstrating that MEI4's DNA-binding activity is required for its reproductive function. In vitro DNA interaction assay with variant MEI4 proteins, knock-in mouse model generation, oogenesis phenotype analysis Human genetics Medium 38252283
2025 The MEI4 C-terminus is required for stabilizing the MEI4–REC114 subcomplex on chromosome axes; Mei4Arg356* (C-terminal truncation) mice exhibit severe DSB formation defects, massive oocyte apoptosis via a HORMAD1-dependent synapsis checkpoint, and surviving oocytes show aneuploidy-driven complete embryonic arrest; heterozygous mice show intermediate follicle depletion consistent with haploinsufficiency. Exome sequencing of POI patients, in vitro DSB formation assay, knock-in mouse model (Mei4Arg356*), cytological analysis, embryonic development assay Journal of genetics and genomics Medium 41419020
2025 Mre11 is recruited to meiotic DSB sites via its C-terminal IDR, which contains a short α-helix that binds a conserved region of Mer2; this interaction is required for Mre11 foci formation during meiosis and DSB formation; the Mer2 interaction is part of the RMM (Rec114-Mei4-Mer2) condensation-dependent recruitment mechanism for Mre11. In vitro condensate assay, mutagenesis of Mer2-binding helix in Mre11, in vivo foci analysis bioRxivpreprint Medium bio_10.1101_2025.07.08.663703

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Functional conservation of Mei4 for meiotic DNA double-strand break formation from yeasts to mice. Genes & development 164 20551173
1998 The Schizosaccharomyces pombe mei4+ gene encodes a meiosis-specific transcription factor containing a forkhead DNA-binding domain. Molecular and cellular biology 118 9528784
2007 Interactions between Mei4, Rec114, and other proteins required for meiotic DNA double-strand break formation in Saccharomyces cerevisiae. Chromosoma 111 17558514
2006 Saccharomyces cerevisiae Mer2, Mei4 and Rec114 form a complex required for meiotic double-strand break formation. Genetics 92 16783010
2000 Autoregulated expression of Schizosaccharomyces pombe meiosis-specific transcription factor Mei4 and a genome-wide search for its target genes. Genetics 88 10747048
2018 Mouse REC114 is essential for meiotic DNA double-strand break formation and forms a complex with MEI4. Life science alliance 80 30569039
1989 MEI4, a yeast gene required for meiotic recombination. Genetics 64 2693205
2015 MEI4 – a central player in the regulation of meiotic DNA double-strand break formation in the mouse. Journal of cell science 58 25795304
1992 MEI4, a meiosis-specific yeast gene required for chromosome synapsis. Molecular and cellular biology 51 1545815
2005 Rad3-Cds1 mediates coupling of initiation of meiotic recombination with DNA replication. Mei4-dependent transcription as a potential target of meiotic checkpoint. The Journal of biological chemistry 27 16286472
2011 Functional interactions of Rec24, the fission yeast ortholog of mouse Mei4, with the meiotic recombination-initiation complex. Journal of cell science 21 21429938
2023 Evolutionary conservation of the structure and function of meiotic Rec114-Mei4 and Mer2 complexes. Genes & development 19 37442581
2023 Characterization of the REC114-MEI4-IHO1 complex regulating meiotic DNA double-strand break formation. The EMBO journal 18 37431931
2023 Structure and DNA-bridging activity of the essential Rec114-Mei4 trimer interface. Genes & development 13 37442580
2011 A novel fission yeast mei4 mutant that allows efficient synchronization of telomere dispersal and the first meiotic division. Yeast (Chichester, England) 11 21449049
2024 Bi-allelic missense variants in MEI4 cause preimplantation embryonic arrest and female infertility. Human genetics 10 38252283
2014 Meiotic nuclear movements in fission yeast are regulated by the transcription factor Mei4 downstream of a Cds1-dependent replication checkpoint pathway. Genes to cells : devoted to molecular & cellular mechanisms 10 25492408
2020 Genetic Interactions of Histone Modification Machinery Set1 and PAF1C with the Recombination Complex Rec114-Mer2-Mei4 in the Formation of Meiotic DNA Double-Strand Breaks. International journal of molecular sciences 6 32290544
2016 Cuf2 Is a Transcriptional Co-Regulator that Interacts with Mei4 for Timely Expression of Middle-Phase Meiotic Genes. PloS one 3 26986212
2023 Structure and DNA bridging activity of the essential Rec114â€"Mei4 trimer interface. bioRxiv : the preprint server for biology 1 36711595
2026 Mei4 deficiency induces sexual dimorphism in early meiosis and promotes production of unreduced eggs in zebrafish. Zoological research 0 42011758
2025 MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential. Journal of genetics and genomics = Yi chuan xue bao 0 41419020

Missed literature

Know a paper Affinage missed for MEI4? Flag it for the maintainers and the community.

No submissions yet.