Affinage

MLH3

DNA mismatch repair protein Mlh3 · UniProt Q9UHC1

Length
1453 aa
Mass
163.7 kDa
Annotated
2026-06-10
55 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MLH3 is the catalytic partner of MLH1 in the MutLγ heterodimer, a metal-dependent endonuclease that drives the resolution of recombination intermediates into crossovers and contributes to a defined subset of post-replicative mismatch repair (PMID:10615123, PMID:9770499, PMID:24403070, PMID:24443562). In meiosis, MLH3 is required to recruit MLH1 to prophase-I chromosomes from mid-pachynema, and its loss renders mice sterile through failure to complete meiosis I (PMID:12091911); MutLγ acts predominantly at recombination hot spots to generate the major (interference-dependent) class of crossovers, with the bulk of crossing-over and chiasmata lost in its absence (PMID:18430927, PMID:31170160). Catalysis depends on a conserved DQHA(X)2E(X)4E endonuclease motif and on ATP hydrolysis, and active-site or ATPase mutations cripple both crossover formation and MMR (PMID:18505871, PMID:23316435, PMID:31170160). Rather than acting as a canonical structure-specific resolvase, MutLγ binds DNA with high affinity—showing marked preference for the open, unstacked form of Holliday junctions—and generates nicks through a polymer-formation mechanism that allows cleavage in trans (PMID:24443562, PMID:28453523, PMID:34088835). Its endonuclease is activated and targeted by partner complexes: MutSγ (MSH4-MSH5) binds branched joint molecules and stimulates nicking, EXO1 serves as a structural scaffold tethering MutSγ-MutLγ to dsDNA via its MSH4 interaction, and RFC-PCNA further license crossing over, with strand incision directed opposite a DNA loop in the MutSβ (MSH2-MSH3)-stimulated reaction (PMID:32814904, PMID:40319035, PMID:32015124). The same endonuclease activity has pathological and somatic consequences: MutLγ working with MutSβ is a principal driver of somatic trinucleotide repeat expansion in Huntington disease, Friedreich ataxia, and Fragile X models, where only the endonuclease-competent MLH3 isoform supports expansion (PMID:24204323, PMID:29529236, PMID:33751106, PMID:32619224), and MLH3 also promotes homologous recombination in human somatic cells by processing joint molecules (PMID:33453991). In mismatch repair, MLH1-MLH3 substitutes for MLH1-PMS2 in correcting specific insertion/deletion mispairs and is partially redundant with PMS2, with its loss producing microsatellite instability and tumor susceptibility (PMID:9770499, PMID:16204034, PMID:10615123), and MLH3 additionally shapes immunoglobulin class switch recombination and somatic hypermutation (PMID:16622010, PMID:16564751).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Established that MLH3 is a MutL-family partner of MLH1 that handles a specific genetic arm of mismatch repair, defining a heterodimer distinct from MLH1-PMS1.

    Evidence Yeast two-hybrid and frameshift-reporter epistasis in S. cerevisiae

    PMID:9770499

    Open questions at the time
    • Did not establish biochemical activity of the complex
    • Mammalian relevance not yet shown
  2. 2000 High

    Extended the MLH1 interaction and MMR role to human cells, showing MLH3 dysfunction causes microsatellite instability.

    Evidence Nuclear extract interaction probing and dominant-negative cell line with MSI assay

    PMID:10615123

    Open questions at the time
    • Catalytic mechanism unknown
    • Did not address meiotic function
  3. 2002 High

    Revealed a dedicated meiotic role: MLH3 recruits MLH1 to chromosomes and is essential for fertility, linking it to MutSγ-dependent recombination.

    Evidence Mlh3 knockout mice with chromosome-spread immunofluorescence; Co-IP with MSH4

    PMID:12091911 PMID:12095912

    Open questions at the time
    • Molecular activity at recombination intermediates not defined
    • MSH4 interaction was Medium-confidence Co-IP
  4. 2005 High

    Quantified the MMR contribution in vivo and showed functional redundancy with PMS2, with MLH3 loss driving tumorigenesis.

    Evidence Single and double knockout mice with MSI, DNA-damage, and tumor assays

    PMID:16204034

    Open questions at the time
    • Mechanistic basis of redundancy not resolved at protein level
  5. 2006 Medium

    Broadened MLH3 function to antibody diversification, showing it shapes class switch junctions and constrains somatic hypermutation.

    Evidence Mlh3-/- B cell switching assays and switch/variable-region sequencing

    PMID:16564751 PMID:16622010

    Open questions at the time
    • Direct enzymatic role in CSR/SHM not demonstrated
    • Single-lab observations
  6. 2008 High

    Pinpointed the endonuclease motif and ATPase activity as required for both meiotic crossover and MMR, separating catalysis from MLH1 binding.

    Evidence Active-site and ATPase mutagenesis in yeast with meiotic and MMR readouts; sperm-typing at a defined hot spot in mice

    PMID:18430927 PMID:18505871 PMID:23316435

    Open questions at the time
    • Endonuclease activity not yet reconstituted in vitro
    • Substrate preference unknown
  7. 2014 High

    Reconstituted MutLγ as a metal-dependent, MSH-stimulated endonuclease with conserved preference for Holliday junctions, providing the biochemical basis for its in vivo roles.

    Evidence Purified yeast and human MLH1-MLH3 with nuclease and Holliday-junction binding assays; Msh2-Msh3 stimulation

    PMID:24403070 PMID:24443562

    Open questions at the time
    • Mechanism of nicking (resolvase vs. other) unresolved
    • How junction preference is achieved structurally unknown
  8. 2017 High

    Defined the catalytic mechanism as polymer-based trans-cleavage rather than canonical structure-specific resolution, and genetically separated MMR from crossover functions.

    Evidence Barrier-substrate and mixed-complex trans-cleavage assays; 60-allele structure-function library with genome-wide recombination mapping

    PMID:28453523 PMID:28827832

    Open questions at the time
    • Structural model of the polymer not defined
    • In vivo regulation of polymerization unclear
  9. 2018 High

    Showed isoform-specific endonuclease dependence of repeat expansion, opening a splice-switching therapeutic route.

    Evidence Knockdown and splice-switching oligonucleotides in Friedreich ataxia cell models and patient fibroblasts

    PMID:29529236

    Open questions at the time
    • In vivo efficacy not addressed in this study
  10. 2019 High

    Separated MutLγ loading from catalysis in vivo, showing the endonuclease itself, not complex assembly, drives crossover maturation and that MUS81-EME1 partially compensates.

    Evidence Mlh3 endonuclease-dead knock-in mouse with meiotic marker cytology and Mus81 double-mutant analysis

    PMID:31170160

    Open questions at the time
    • Timing of incision relative to junction formation incompletely defined
  11. 2020 High

    Built the complete meiotic resolvase ensemble, defining how MutSγ, EXO1, and RFC-PCNA activate and target MutLγ incision at joint molecules.

    Evidence Reconstitution of MutLγ-MutSγ-EXO1-RFC-PCNA with cleavage assays and yeast PCNA-interaction mutants; loop-substrate strand-specificity and cell-extract expansion assays

    PMID:32015124 PMID:32619224 PMID:32814904

    Open questions at the time
    • Stoichiometry and architecture of the in vivo ensemble not fully resolved
  12. 2021 High

    Provided a structural framework (filament-like assemblies, Mlh1 C-terminus completing the active site) and extended endonuclease dependence to in vivo repeat expansion and somatic HR.

    Evidence Crystal structure of MutLγ CTD with interface mutagenesis; endonuclease-dead knock-in HD mice and splice-switching; HR/SCE assays in human TK6 cells with GEN1 rescue

    PMID:33453991 PMID:33751106 PMID:34088835

    Open questions at the time
    • Full-length complex structure absent
    • How polymer interfaces are regulated in cells unknown
  13. 2024 Medium

    Identified Dmc1 as a recruitment/activation factor coupling MutLγ to recombination intermediates at the resolution stage.

    Evidence Yeast in vitro pull-down, in vivo Co-IP, dosage screen, and promoter-swap crossover assays

    PMID:38657110

    Open questions at the time
    • Direct mechanism of Dmc1-mediated recruitment not reconstituted
    • Single lab
  14. 2025 High

    Resolved EXO1's role as a non-catalytic structural scaffold bridging MutSγ-MutLγ to dsDNA, decoupling its activation function from its intrinsic nuclease.

    Evidence Reconstitution and point mutagenesis (EXO1 W371E) with DNA nicking and interaction-mapping assays

    PMID:40319035

    Open questions at the time
    • In vivo validation of the scaffolding model limited
    • Single lab
  15. 2026 Medium

    Suggested non-canonical MLH3 roles in oocyte spindle/checkpoint integrity and endometrial decidualization beyond recombination.

    Evidence Trim-Away depletion in mouse oocytes with spindle/BubR1 imaging and embryo transfer; siRNA in human endometrial stromal cells

    PMID:42000973

    Open questions at the time
    • Mechanistic link between endonuclease activity and spindle/decidualization phenotypes unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MutLγ incision is spatially and temporally licensed to produce interference-patterned crossovers in vivo, and the structure of the full-length active ensemble, remain unresolved.
  • No full-length MutLγ-MutSγ-EXO1 structure
  • Mechanism coupling incision to crossover interference unknown
  • Centrosome and meiotic-spindle roles mechanistically uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 5 GO:0016787 hydrolase activity 3 GO:0003677 DNA binding 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 1
Pathway
R-HSA-1474165 Reproduction 4 R-HSA-1643685 Disease 4 R-HSA-73894 DNA Repair 3 R-HSA-168256 Immune System 2
Partners
DMC1EXO1MLH1MSH2MSH3MSH4MSH5PCNA
Complex memberships
MutLγ (MLH1-MLH3)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 MLH3 encodes a DNA mismatch repair protein that physically interacts with MLH1, identified by probing nuclear extracts with the conserved carboxy-terminal MLH1 interaction domain; stable expression of a dominant-negative MLH3 protein in cultured cells causes microsatellite instability. Nuclear extract probing with MLH1 interaction domain; dominant-negative stable cell line expression with microsatellite instability assay Nature genetics High 10615123
1998 In S. cerevisiae, MLH3 interacts with MLH1 in a two-hybrid system and functions in the MSH3-dependent mismatch repair pathway; mlh3 mutations increase frameshift mutation rates synergistically with msh6 but not msh3, consistent with MLH1-MLH3 acting as a heterodimeric complex in place of MLH1-PMS1 for repair of specific insertion/deletion mispairs. Yeast two-hybrid; genetic epistasis analysis with frameshift reporter alleles (hom3-10, LYS2) Proceedings of the National Academy of Sciences of the United States of America High 9770499
2002 MLH3 is required for MLH1 binding to meiotic chromosomes in mice; MLH3 localizes to meiotic chromosomes from mid-pachynema of prophase I, and Mlh3-/- mice are sterile with spermatocytes arresting at metaphase and oocytes failing to complete meiosis I. Mlh3 knockout mouse generation; immunofluorescence localization on meiotic chromosome spreads; cytological analysis of spermatocyte and oocyte progression Nature genetics High 12091911
2002 MLH3 protein co-immunoprecipitates with the meiosis-specific MSH4 protein from mouse spermatocyte extracts, and both human MLH3 isoforms interact in vitro with human MSH4, supporting a role for MLH3 in mammalian meiotic recombination. Co-immunoprecipitation from mouse meiotic cell extracts; in vitro interaction assays with human proteins Human molecular genetics Medium 12095912
2002 In meiotic yeast cells, Mlh3 co-immunoprecipitates with Sgs1 helicase (which forms a stable complex with Top3 during meiosis), suggesting that the Mlh1-Mlh3 heterocomplex coordinates with the Sgs1-Top3 complex in resolution of meiotic recombination intermediates. Co-immunoprecipitation from sporulating yeast cells Biochemical and biophysical research communications Low 12200140
2005 Mlh3 deficiency alone in mice causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility; Mlh3;Pms2 double-deficient mice phenocopy Mlh1-deficient mice in tumor susceptibility, lifespan, MSI, and DNA-damage response, demonstrating partial functional redundancy between MLH3 and PMS2 in mismatch repair. Single and double knockout mouse models; microsatellite instability assays; tumor susceptibility analysis; DNA damage response assays Cancer research High 16204034
2006 Mlh3 deficiency in mice alters class switch DNA recombination (CSR) and somatic hypermutation (SHM): Mlh3-/- B cells show preferential targeting of RGYW/WRCY motifs by Sγ breakpoints and altered insertion/microhomology profiles in switch junctions; residual SHM mutations show decreased dA/dT mutations and preferential RGYW/WRCY targeting at dC/dG. In vitro class switching assays with Mlh3-/- B cells; sequencing of switch junctions and immunoglobulin variable region mutations Journal of immunology Medium 16622010
2006 Loss of Mlh3 in mice increases the frequency of somatic hypermutation in immunoglobulin variable regions compared to wild-type, with altered mutation spectra, indicating that Mlh3 normally inhibits accumulation of mutations during SHM. Mlh3-/- mouse analysis; sequencing of JH4 flanking region mutations DNA repair Medium 16564751
2008 Mutations in the conserved endonuclease domain motif DQHA(X)2E(X)4E of yeast MLH3 (D523N, E529K) confer mlh3-null-like defects in meiotic spore viability and crossing over, and a mutator phenotype in vegetative growth similar to mlh3Δ, while the D523N mutation maintains MLH1-MLH3 interaction, demonstrating that the endonuclease domain is required for both MMR and meiotic crossover functions. Site-directed mutagenesis; yeast two-hybrid; chromatography-based interaction assay; meiotic spore viability and crossing-over assays; dominant-negative overexpression Genetics High 18505871
2008 MLH3 functions at meiotic recombination hot spots predominantly with MLH1 to promote crossovers; Mlh3-/- spermatocytes show 85-94% reduction in crossovers at the Psmb9 hot spot with an increase in noncrossover events, while approximately 10% of crossovers are MLH3-independent. PCR-based sperm typing at the Psmb9 hot spot in Mlh3-/- mice; quantification of crossovers and noncrossovers Genetics High 18430927
2008 In Mus81-/- mice, MLH1 accumulates on pachytene chromosomes at elevated levels in an interference-independent fashion, suggesting that MLH1-MLH3-dependent and MUS81 crossover pathways are integrated and regulate each other's activity. Mus81-/- mouse analysis; immunofluorescence quantification of MLH1 foci on meiotic chromosome spreads; chiasmata counting PLoS genetics Medium 18787696
2013 Mlh3 deficiency abolishes somatic HTT CAG repeat expansion in Huntington's disease Hdh(Q111) mice (as does Mlh1 deficiency), identifying the MutLγ (MLH1-MLH3) complex as a key driver of somatic CAG expansion alongside the MutSβ (MSH2-MSH3) mismatch recognition complex. Mlh3 null mouse cross onto Hdh(Q111) background; somatic CAG expansion quantification by tissue DNA analysis; linkage mapping PLoS genetics High 24204323
2013 Mlh3 ATPase domain mutations in yeast disrupt both meiotic crossing over and MMR, and mlh3Δ mms4Δ double mutants show 6- to 17-fold reductions in crossing over across multiple chromosomes, supporting a role for ATP hydrolysis by both Mlh1 and Mlh3 in meiotic and MMR functions. Structure-function analysis of ATPase mlh3 alleles; genetic map construction across four chromosomes; spore viability analysis G3 (Bethesda, Md.) Medium 23316435
2014 Purified yeast Mlh1-Mlh3 (MutLγ) heterodimer is a metal-dependent, Msh2-Msh3-stimulated endonuclease that makes single-strand breaks in supercoiled DNA, directly supporting its role in resolving recombination intermediates and in DNA mismatch repair. Recombinant protein purification; in vitro endonuclease assay on supercoiled DNA; stimulation assay with Msh2-Msh3 The Journal of biological chemistry High 24403070
2014 Purified yeast and human MLH1-MLH3 (MutLγ) heterodimers are nucleases that nick double-stranded DNA and bind DNA with high affinity, showing marked preference for Holliday junctions (specifically the open unstacked form); this Holliday junction-binding preference is conserved in human MutLγ and is not seen with other eukaryotic MutL homologs. Recombinant protein expression and purification (yeast and human); in vitro nuclease assay; DNA binding/EMSA with Holliday junctions and linear DNA The Journal of biological chemistry High 24443562
2017 Mlh1-Mlh3 endonuclease activity requires polymer formation: DNA binding studies with polymerization barriers and mixing of endonuclease-deficient and -proficient complexes demonstrate that Mlh1-Mlh3 forms polymers to generate nicks, can cleave DNA substrates in trans, and does not act as a canonical structure-specific endonuclease. In vitro endonuclease assays with barrier-containing substrates; mixed endonuclease-deficient/proficient complex assays (trans-cleavage); DNA binding studies PLoS biology High 28453523
2017 Structure-function analysis of 60 yeast mlh3 alleles separates MMR and crossover functions: allele mlh3-32 specifically disrupts crossover without affecting MMR, while mlh3-45 disrupts MMR without affecting crossovers. Msh2-Msh3 stimulates endonuclease activity of Mlh1-mlh3-32 but not Mlh1-mlh3-45, indicating mlh3-45 is defective in MSH interactions. All mlh3 mutants show increased noncrossovers genome-wide. Allele library generation; in vitro endonuclease assays; whole-genome recombination mapping in S288c/YJM789 hybrids; Msh2-Msh3 stimulation assays PLoS genetics High 28827832
2018 MutLγ (MLH1-MLH3) is the specific MutL complex responsible for GAA•TTC repeat expansion; MLH3 isoform 1 (containing the endonuclease domain) is active in expansion while MLH3 isoform 2 (nuclease-deficient) is not. Splice-switching oligonucleotides that redirect MLH3 splicing to the nuclease-deficient isoform slow repeat expansion in Friedreich ataxia model cells and patient fibroblasts. shRNA knockdown of MLH1, PMS2, MLH3; splice-switching oligonucleotides; repeat expansion assay in human Friedreich ataxia cell model and patient fibroblasts Nucleic acids research High 29529236
2019 A mouse harboring a catalytic-inactivating point mutation in the MLH3 endonuclease domain (Mlh3DN/DN) is infertile with reduced chiasmata (22% of wild-type vs. 10% in Mlh3-/- males), normal loading frequency of MutLγ in pachynema (unlike Mlh3-/- null), but persistent RAD51 and BLM helicase into pachynema indicating temporal delay in DSB repair. Double mutant Mlh3DN/DN;Mus81-/- spermatocytes show chiasmata levels close to Mlh3-/-, indicating MUS81-EME1 pathway partially compensates in Mlh3DN/DN. Knock-in mouse with endonuclease-domain point mutation; immunofluorescence of meiotic markers (RAD51, BLM, MutLγ, MutSγ, CDK2, HEI10); chiasmata counting; double mutant analysis PLoS genetics High 31170160
2020 Human MutLγ (MLH1-MLH3) is an endonuclease that nicks DNA; incision of covalently closed, relaxed loop-containing DNA is promoted by MutSβ (MSH2-MSH3) and targeted to the strand opposite the loop, and the resulting strand break licenses DNA expansion events in human cell extracts. Purified recombinant human MLH1-MLH3; in vitro endonuclease assay on loop-containing substrates; strand-specificity analysis; DNA expansion assay in human cell extracts Proceedings of the National Academy of Sciences of the United States of America High 32015124
2020 Human MSH4-MSH5 (MutSγ) binds branched recombination intermediates and associates with MutLγ (MLH1-MLH3), stabilizing the ensemble at joint molecule structures; MutSγ directly stimulates MutLγ endonuclease activity; EXO1 further stimulates MutLγ only when MutSγ is present; RFC and PCNA are additional components that trigger crossing over. MutLγ cannot interact with PCNA in yeast strains that show crossover defects. The MutLγ-MutSγ-EXO1-RFC-PCNA ensemble preferentially cleaves DNA with Holliday junctions by nicking dsDNA adjacent to junction points rather than canonical resolvase activity. Biochemical reconstitution of the endonuclease ensemble; DNA binding and cleavage assays; PCNA interaction mutants in yeast; meiotic crossover analysis in yeast PCNA-interaction mutants Nature High 32814904
2020 A point mutation abolishing MLH3 endonuclease activity eliminates CGG repeat expansions in a Fragile X-related disorder mouse embryonic stem cell model, demonstrating that the MLH3 endonuclease domain is required for repeat expansion. Gene editing to introduce nuclease-dead point mutation in MLH3 in mouse ES cells; repeat expansion assay Nucleic acids research High 32619224
2021 Crystal structure of the S. cerevisiae MutLγ C-terminal domain (CTD) reveals overall similarity to MutLα(CTD) but with rearrangements of the surface surrounding the active site indicating altered substrate preference; the extreme C-terminus of Mlh1 participates in the Mlh3 endonuclease site; MutLγ(CTD) preferentially binds Holliday junctions (unlike MutLα(CTD)); crystal packing reveals filament-like assemblies and mutations at these interfaces reduce crossover formation. X-ray crystallography of MutLγ CTD; mlh1 allele functional analysis in MMR and meiotic recombination; Holliday junction binding assays; in vivo crossover assays with interface mutants Proceedings of the National Academy of Sciences of the United States of America High 34088835
2021 A point mutation in the MLH3 endonuclease domain completely eliminates somatic CAG repeat expansion in brain and peripheral tissues of Huntington's disease HttQ111 knock-in mice; splice-switching oligonucleotides that redirect Mlh3 splicing to exclude the endonuclease domain reduce CAG expansion in mice and HD patient-derived fibroblasts. Mlh3 endonuclease-dead knock-in mouse; splice-switching oligonucleotide delivery in vivo; CAG repeat sizing assays in multiple tissues; HD patient fibroblast experiments Nucleic acids research High 33751106
2021 MLH3 and PMS2 endonucleases promote homologous recombination in human somatic (TK6) cells: MLH3-/- and MLH3DN/DN cells show ~2.5-fold decrease in heteroallelic HR-dependent repair; double MLH3DN/DN;PMS2EK/EK cells show delayed Rad51 focus resolution, reduced sister chromatid exchanges, and partial rescue by GEN1 HJ resolvase overexpression, indicating MLH3 promotes HR by processing joint molecules as an endonuclease. Gene knockout and endonuclease-dead knock-in in human TK6 cells; restriction enzyme-induced DSB repair assay; Rad51 focus kinetics; SCE assay; GEN1 rescue experiment The Journal of biological chemistry High 33453991
2014 MLH3 localizes to centrosomes in human cell lines as detected by live cell imaging of GFP-MLH3; FRAP analysis shows high mobility and fast exchange at centrosomes, suggesting a possible role with other repair proteins in centrosome number control. Stable GFP-MLH3 expression; live cell confocal imaging; fluorescence recovery after photobleaching (FRAP) International journal of molecular sciences Low 25116689
2024 Yeast Mlh3 physically interacts with the meiotic recombinase Dmc1 in vitro and in vivo (co-IP); gene dosage screen identified MLH3-DMC1 genetic interactions; restricting MLH3 expression to the time of crossover resolution (CLB1 promoter) resulted in partial crossover function loss, consistent with Dmc1 facilitating Mlh1-Mlh3 recruitment to or polymer formation at recombination intermediates. Gene dosage (haploinsufficiency) screen with sensitized mlh3 alleles; in vitro pull-down; co-immunoprecipitation in vivo; promoter-swap expression analysis; meiotic crossover assays Genetics Medium 38657110
2025 EXO1 directly interacts with MLH1 via its MIP motif and also directly interacts with MSH4 (MutSγ); a single EXO1 point mutation (W371E) that impairs MSH4 interaction completely abolishes EXO1's ability to activate MutLγ DNA nicking without affecting EXO1 intrinsic nuclease activity; disruption of EXO1 dsDNA-interacting residues reduces MutSγ-MutLγ activity, identifying EXO1 as a structural scaffold in the meiotic resolvase complex tethering MutSγ-MutLγ to dsDNA. Biochemical reconstitution of MutLγ-MutSγ-EXO1 complex; point mutagenesis; in vitro DNA nicking assays; interaction mapping Nature communications High 40319035
2026 Mlh3 depletion (via Trim-Away) in mouse GV-stage oocytes disrupts spindle assembly, mislocalizes the spindle assembly checkpoint kinase BubR1, and induces focal chromosomal imbalances in early embryos, leading to impaired blastocyst development and high post-implantation pregnancy loss; MLH3 knockdown in human endometrial stromal cells impairs decidualization and alters proliferation-apoptosis homeostasis. Trim-Away-mediated Mlh3 protein depletion in mouse oocytes; spindle immunofluorescence; BubR1 localization; embryo transfer; siRNA knockdown in human endometrial stromal cells Cellular and molecular life sciences Medium 42000973

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Meiotic arrest and aneuploidy in MLH3-deficient mice. Nature genetics 314 12091911
2000 MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nature genetics 253 10615123
1998 The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations. Proceedings of the National Academy of Sciences of the United States of America 237 9770499
2013 Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches. PLoS genetics 202 24204323
2008 MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. PLoS genetics 164 18787696
2001 A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nature genetics 124 11586295
2020 Regulation of the MLH1-MLH3 endonuclease in meiosis. Nature 121 32814904
2008 A mutation in the putative MLH3 endonuclease domain confers a defect in both mismatch repair and meiosis in Saccharomyces cerevisiae. Genetics 111 18505871
2014 Mlh1-Mlh3, a meiotic crossover and DNA mismatch repair factor, is a Msh2-Msh3-stimulated endonuclease. The Journal of biological chemistry 110 24403070
2014 The Saccharomyces cerevisiae Mlh1-Mlh3 heterodimer is an endonuclease that preferentially binds to Holliday junctions. The Journal of biological chemistry 96 24443562
2005 Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer research 83 16204034
2002 The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination. Human molecular genetics 83 12095912
2020 Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion. Proceedings of the National Academy of Sciences of the United States of America 69 32015124
2017 The mismatch repair and meiotic recombination endonuclease Mlh1-Mlh3 is activated by polymer formation and can cleave DNA substrates in trans. PLoS biology 67 28453523
2001 Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers. Human mutation 59 11317354
2018 Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition. Genetics in medicine : official journal of the American College of Medical Genetics 51 30573798
2008 Distinct functions of MLH3 at recombination hot spots in the mouse. Genetics 47 18430927
2018 GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one. Nucleic acids research 39 29529236
2000 Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer. The American journal of pathology 39 10934138
2003 Little evidence for involvement of MLH3 in colorectal cancer predisposition. International journal of cancer 37 12800209
2021 Somatic CAG expansion in Huntington's disease is dependent on the MLH3 endonuclease domain, which can be excluded via splice redirection. Nucleic acids research 33 33751106
2008 Novel roles for MLH3 deficiency and TLE6-like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression. PLoS genetics 30 18551179
2006 A role for the MutL mismatch repair Mlh3 protein in immunoglobulin class switch DNA recombination and somatic hypermutation. Journal of immunology (Baltimore, Md. : 1950) 30 16622010
2021 Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation. Proceedings of the National Academy of Sciences of the United States of America 29 34088835
2020 A point mutation in the nuclease domain of MLH3 eliminates repeat expansions in a mouse stem cell model of the Fragile X-related disorders. Nucleic acids research 29 32619224
2017 mlh3 mutations in baker's yeast alter meiotic recombination outcomes by increasing noncrossover events genome-wide. PLoS genetics 28 28827832
2002 Supercomplex formation between Mlh1-Mlh3 and Sgs1-Top3 heterocomplexes in meiotic yeast cells. Biochemical and biophysical research communications 28 12200140
2019 A mutation in the endonuclease domain of mouse MLH3 reveals novel roles for MutLγ during crossover formation in meiotic prophase I. PLoS genetics 26 31170160
2008 The first functional study of MLH3 mutations found in cancer patients. Genes, chromosomes & cancer 25 18521850
2013 Genetic analysis of mlh3 mutations reveals interactions between crossover promoting factors during meiosis in baker's yeast. G3 (Bethesda, Md.) 24 23316435
2006 MLH3 mutation in endometrial cancer. Cancer research 24 16885347
2020 Genetic evidence for the involvement of mismatch repair proteins, PMS2 and MLH3, in a late step of homologous recombination. The Journal of biological chemistry 22 33453991
2018 The polymorphisms of miRNA-binding site in MLH3 and ERCC1 were linked to the risk of colorectal cancer in a case-control study. Cancer medicine 20 29516665
2021 Rice MutLγ, the MLH1-MLH3 heterodimer, participates in the formation of type I crossovers and regulation of embryo sac fertility. Plant biotechnology journal 19 33544956
2006 A role for Mlh3 in somatic hypermutation. DNA repair 19 16564751
2021 A loss-of-function variant in DNA mismatch repair gene MLH3 underlies severe oligozoospermia. Journal of human genetics 16 33517345
2009 Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome. Genes, chromosomes & cancer 16 19156873
2004 No association between two MLH3 variants (S845G and P844L)and colorectal cancer risk. Cancer genetics and cytogenetics 15 15193445
2014 Mismatch repair gene MLH3 Pro844Leu and Thr942Ile polymorphisms and the susceptibility to cervical carcinoma and HPV infection: a case-control study in a Chinese population. PloS one 13 24759751
2015 Single-nucleotide polymorphism rs 175080 in the MLH3 gene and its relation to male infertility. Journal of assisted reproduction and genetics 12 26520453
2013 Analysis of MLH3 C2531T polymorphism in Iranian women with unexplained infertility. Iranian journal of reproductive medicine 10 24639688
2015 Genetic and epigenetic characterization of low-grade gliomas reveals frequent methylation of the MLH3 gene. Genes, chromosomes & cancer 9 26303387
2017 Embryological Results of Couples Undergoing ICSI-ET Treatments with Males Carrying the Single Nucleotide Polymorphism rs175080 of the MLH3 Gene. International journal of molecular sciences 7 28157160
2006 Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer. World journal of gastroenterology 7 16981255
2025 EXO1 promotes the meiotic MLH1-MLH3 endonuclease through conserved interactions with MLH1, MSH4 and DNA. Nature communications 5 40319035
2014 Localization of MLH3 at the centrosomes. International journal of molecular sciences 5 25116689
2012 Expression analysis of MLH3, MLH1, and MSH4 in maturation arrest. Reproductive sciences (Thousand Oaks, Calif.) 5 22344730
2009 Tissue culture-induced variation at simple sequence repeats in sorghum (Sorghum bicolor L.) is genotype-dependent and associated with down-regulated expression of a mismatch repair gene, MLH3. Plant cell reports 5 19908047
2017 Reduced MLH3 Expression in the Syndrome of Gan-Shen Yin Deficiency in Patients with Different Diseases. Evidence-based complementary and alternative medicine : eCAM 4 29234393
2015 An infant with MLH3 variants, FOXG1-duplication and multiple, benign cranial and spinal tumors: A clinical exome sequencing study. Genes, chromosomes & cancer 4 26542077
2025 A Novel Case of Biallelic MLH3 Variants in a Patient With Rectal Cancer and Polyps. Clinical genetics 3 39789695
2024 The Dmc1 recombinase physically interacts with and promotes the meiotic crossover functions of the Mlh1-Mlh3 endonuclease. Genetics 3 38657110
2025 Follow-up of hereditary endometrial carcinoma caused by MLH3 gene mutation: a case report. Frontiers in oncology 1 40356752
2026 Maternal MLH3 dysfunction drives unexplained recurrent pregnancy loss via impaired oocyte maturation and defective decidualization. Cellular and molecular life sciences : CMLS 0 42000973
2023 The Dmc1 recombinase physically interacts with and promotes the meiotic crossover functions of the Mlh1-Mlh3 endonuclease. bioRxiv : the preprint server for biology 0 38014100

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