Affinage

MLH1

DNA mismatch repair protein Mlh1 · UniProt P40692

Round 2 corrected
Length
756 aa
Mass
84.6 kDa
Annotated
2026-04-28
130 papers in source corpus 27 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MLH1 is a central component of the eukaryotic DNA mismatch repair (MMR) system and a key determinant of meiotic crossover resolution. As part of the MutLα heterodimer (MLH1–PMS2), it functions as a latent endonuclease activated by MutSα, RFC, PCNA, and ATP to nick the error-containing strand during post-replicative MMR, with the catalytic site residing in PMS2 but MLH1 ATPase activity required for function (PMID:16873062, PMID:11897781). As part of MutLγ (MLH1–MLH3), it forms a Holliday junction–preferring endonuclease stimulated by MutSγ, EXO1, RFC, and PCNA to resolve meiotic recombination intermediates into crossovers (PMID:32814904, PMID:24443562). Germline loss-of-function mutations in MLH1 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), and MLH1 deficiency leads to microsatellite instability, meiotic failure, deregulated Exo1-dependent excision triggering cGAS–STING innate immune signaling, and impaired apoptotic responses to alkylation and platinum damage (PMID:8145827, PMID:8673133, PMID:33338427, PMID:13679151).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1994 High

    Identification of MLH1 as the chromosome 3p-linked hereditary nonpolyposis colorectal cancer gene established that defects in a human MutL homologue directly cause familial cancer predisposition with microsatellite instability.

    Evidence Positional cloning and mutation analysis in HNPCC kindreds, concurrent studies

    PMID:8128251 PMID:8145827

    Open questions at the time
    • Biochemical function of MLH1 protein not yet demonstrated
    • Spectrum of pathogenic versus benign variants undefined
  2. 1994 High

    Demonstration that yeast Mlh1 and Pms1 form a heterodimer that joins MSH2 on mismatch-containing DNA established the ternary MutS–MutL–heteroduplex complex as the initiating unit of eukaryotic MMR.

    Evidence Co-immunoprecipitation and DNA-binding assays with purified yeast proteins on G-T mismatch substrates

    PMID:8066446

    Open questions at the time
    • Catalytic activity of the MutL complex not yet identified
    • Human MutLα not yet reconstituted
  3. 1996 High

    Mlh1 knockout mice revealed that MLH1 is essential for both somatic MMR (microsatellite instability, tumor predisposition) and meiotic crossover formation (infertility, pachytene arrest), establishing dual in vivo roles.

    Evidence Two independent gene-targeted mouse models with cytogenetics, immunolocalization on meiotic chromosomes, and in vitro MMR assay on cell extracts

    PMID:8673133 PMID:8674118

    Open questions at the time
    • Molecular basis for MLH1 localization to crossover sites unknown
    • Whether MutLα and MutLγ have distinct enzymatic activities unclear
  4. 2002 High

    Mutational analysis of MLH1 ATPase and C-terminal dimerization domains separated the requirements for MutLα assembly from those for catalytic MMR function, showing that N-terminal ATPase activity is essential for repair independently of heterodimerization.

    Evidence In vitro MMR complementation assays with ATPase and dimerization-deficient mutants of human MutLα expressed in insect cells

    PMID:11793442 PMID:11897781

    Open questions at the time
    • What the ATPase-driven conformational change accomplishes mechanistically was unknown
    • Endonuclease activity not yet discovered
  5. 2003 High

    MLH1 haploinsufficiency was shown to switch cell fate from apoptosis to mutagenesis after alkylation damage, revealing that cellular MMR protein dosage is a critical determinant of the DNA damage response.

    Evidence Isogenic Mgmt−/−/Mlh1+/− mouse cell lines with HPRT mutation frequency and caspase-3 induction assays after MNU

    PMID:13679151

    Open questions at the time
    • Signaling pathway linking MMR recognition to apoptosis not defined
    • Threshold MLH1 level for repair versus tolerance not quantified
  6. 2006 High

    The discovery that human MutLα is a latent endonuclease—activated by MutSα, RFC, PCNA, and ATP to nick the discontinuous strand—resolved the long-standing question of how eukaryotic MMR introduces strand breaks, with the active site mapped to the PMS2 DQHA(X)₂E(X)₄E motif.

    Evidence In vitro reconstitution of MutLα endonuclease activity on heteroduplex DNA with active-site mutagenesis and strand-specific nicking assays

    PMID:16873062

    Open questions at the time
    • How MLH1 contributes to endonuclease activation versus serving as a scaffold unclear
    • Structural basis of PCNA-dependent activation unknown
  7. 2009 High

    Post-translational regulation of MLH1 was established when HDAC6-mediated deacetylation of four MLH1 acetylation sites was shown to block MutSα–MutLα assembly, providing a mechanism for modulating MMR competence.

    Evidence Co-IP, in vitro deacetylation, mass spectrometry of acetylation sites, deacetylation-mimetic mutant conferring 6-thioguanine resistance

    PMID:30770470

    Open questions at the time
    • Which acetyltransferase(s) acetylate MLH1 not identified
    • In vivo stoichiometry of acetylated versus deacetylated MLH1 unknown
  8. 2014 High

    Biochemical reconstitution of MutLγ (MLH1–MLH3) as a Holliday junction–preferring endonuclease, conserved from yeast to human, distinguished MutLγ from MutLα and linked it directly to the crossover-specific resolution machinery.

    Evidence Purified recombinant yeast and human MLH1–MLH3 endonuclease assays with Holliday junction substrates

    PMID:24443562

    Open questions at the time
    • Whether MutLγ acts as a classical resolvase or nicks adjacent dsDNA was unresolved
    • Regulation of MutLγ by upstream factors not yet reconstituted
  9. 2020 High

    Full reconstitution of the pro-crossover nuclease ensemble (MutSγ–MutLγ–EXO1–RFC–PCNA) showed that MutSγ stimulates MutLγ endonuclease on joint molecules and that PCNA interaction is required for meiotic crossover, resolving how MLH1-containing complexes generate crossovers without canonical resolvase cleavage.

    Evidence Biochemical reconstitution of multi-protein ensemble with DNA cleavage assays; yeast PCNA-interaction mutants with crossover defects

    PMID:32814904

    Open questions at the time
    • Structural basis of MutSγ–MutLγ handoff at Holliday junctions unresolved
    • How nicking is directed to the correct strands in vivo remains unclear
  10. 2020 High

    MLH1 loss was shown to cause unrestrained Exo1 excision during repair, leading to ssDNA accumulation, RPA exhaustion, chromosomal breaks, and cytoplasmic DNA release that activates cGAS–STING, connecting MMR deficiency to innate immune pathway activation.

    Evidence MLH1-knockout cell lines with Exo1 activity assays, ssDNA/RPA foci quantification, cytoplasmic DNA detection, and cGAS–STING reporter assays

    PMID:33338427

    Open questions at the time
    • Whether this pathway contributes to immunotherapy responsiveness of MSI-H tumors not mechanistically tested
    • Direct structural basis for MLH1 restraint of Exo1 unknown
  11. 2024 Medium

    A histone lactylation–LUC7L2 axis was identified that promotes MLH1 intron 7 retention, reducing MLH1 protein and enabling temozolomide resistance, demonstrating RNA processing as a regulatory layer for MLH1 expression in cancer.

    Evidence CUT&Tag, SLAM-seq, RNA-seq, siRNA, and LDHA/B inhibitor rescue in GBM models in vitro and in vivo

    PMID:38477507

    Open questions at the time
    • Whether intron retention is a general mechanism across MLH1-deficient cancers unknown
    • Direct splicing factor binding at intron 7 not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MLH1 allosterically activates the PMS2/MLH3 endonuclease domains, the structural basis of PCNA-mediated licensing of MutLα/MutLγ nicking, and how acetylation/deacetylation dynamics are coordinated with replication timing remain open questions.
  • No high-resolution structure of full-length human MutLα engaged with PCNA on DNA
  • Mechanism by which MLH1 ATPase cycle couples mismatch recognition to endonuclease activation unresolved
  • In vivo regulation of MLH1 acetylation during S-phase not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 4 GO:0003677 DNA binding 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3
Pathway
R-HSA-73894 DNA Repair 7 R-HSA-1474165 Reproduction 5 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
EXO1FANCJHDAC6MLH3MSH2MSH4PCNAPMS2
Complex memberships
BASC (BRCA1-associated genome surveillance complex)MutLα (MLH1–PMS2)MutLγ (MLH1–MLH3)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 hMLH1 was identified as the human homologue of bacterial MutL, located on chromosome 3p21.3-23, with missense mutations found in HNPCC kindreds, establishing it as the chromosome 3-linked HNPCC gene responsible for hereditary nonpolyposis colon cancer. Positional cloning, sequence homology, mutation analysis in HNPCC families Nature High 8128251 8145827
1994 Yeast MLH1 and PMS1 proteins physically associate, likely forming a heterodimer, and act in concert to bind an MSH2-heteroduplex complex containing a G-T mismatch, forming a ternary complex during initiation of eukaryotic DNA mismatch repair. Physical interaction assays (co-immunoprecipitation/pulldown), DNA-binding assays with mismatch-containing heteroduplex Science High 8066446
1996 Mlh1-deficient mice exhibit microsatellite instability and infertility in both sexes; spermatocytes show high levels of prematurely separated chromosomes and arrest in first meiotic division; MLH1 localizes to sites of crossing over on meiotic chromosomes, indicating roles in both DNA mismatch repair and meiotic crossing over. Gene targeting (knockout mice), cytogenetics, immunolocalization on meiotic chromosomes Nature genetics High 8673133 8674118
1996 MLH1-deficient mice show meiotic pachytene arrest in males, with no detectable mature sperm, while females are infertile despite normal estrous cycles; cell extracts are deficient in mismatch repair activity, demonstrating that MLH1 function is required for mismatch repair and meiosis with distinct phenotypes from Msh2 and Pms2 knockouts. Gene targeting (null mutation), in vitro MMR assay on cell extracts, meiotic staging Cell High 8674118
1999 MLH1 overexpression in yeast causes a strong mutator phenotype by inactivating DNA mismatch repair; purified Mlh1p forms a homodimer in solution (Kd ~3.14 µM, 36-fold weaker than Mlh1p-Pms1p heterodimer), and the mutator effect results from imbalance between Mlh1p and Pms1p levels leading to formation of nonfunctional homodimer-containing complexes. Yeast genetics (overexpression), mutation rate assays, analytical ultracentrifugation of purified protein Molecular and cellular biology High 10082584 11154280
2000 Human MSH4 physically interacts with hMLH1 (co-immunoprecipitated independently of DNA or ATP); the interaction domain maps to the N-terminal portion of MSH4; MSH4 and MLH1 colocalize during late pachynema on meiotic chromosomes, suggesting MSH4 acts first in chromosome synapsis then cooperates with MLH1 in meiotic reciprocal recombination. Co-immunoprecipitation, domain mapping, immunolocalization on meiotic chromosomes FASEB journal Medium 10928988
2002 MLH1 ATPase activity (N-terminal conserved glutamic acid residue) is required for mismatch repair; both MLH1 and PMS2 N-terminal domains undergo ATP-induced conformational changes, but MLH1 binds ATP with higher affinity than PMS2; double ATPase mutant shows no detectable MMR activity, while single mutants are partially defective. In vitro MMR assay with insect cell-expressed human MutLα ATPase mutants, limited proteolysis The Journal of biological chemistry High 11897781
2002 MLH1 C-terminal mutations (internal deletions of exon 16 or 17, or R659P missense) abolish formation of functional MutLα (MLH1-PMS2 heterodimer); N-terminal mutations C77R and I107R do not affect heterodimerization but the resulting complexes fail to complement MMR-deficient extracts, indicating that N-terminal domain is critical for MMR activity independent of dimerization. In vitro MMR complementation assay, co-immunoprecipitation for heterodimerization Genes, chromosomes & cancer High 11793442
2003 Nuclear localization of MutLα (MLH1-PMS2 dimer) depends on C-terminal dimerization: MLH1 and PMS2 each have functional NLS and nuclear export sequences, but nuclear import is enhanced by their heterodimerization, which is proposed to unmask the NLS, providing a regulatory mechanism for fine-tuning mismatch repair. Transfection of NLS/NES mutants, subcellular fractionation, confocal microscopy Molecular and cellular biology Medium 12697830
2006 Human MutLα (MLH1·PMS2 heterodimer) is a latent endonuclease activated in a mismatch-, MutSα-, RFC-, PCNA-, and ATP-dependent manner; incision is biased to the nicked strand of a heteroduplex; the endonuclease active site resides in the PMS2 DQHA(X)2E(X)4E motif; a mismatch-containing segment flanked by two breaks is removed by 5'-to-3' exonuclease I activity. In vitro reconstitution of endonuclease activity, active-site mutagenesis, strand-specific nicking assays Cell High 16873062
2009 MLH1 has a bipartite nuclear localization signal and PMS2 has a monopartite NLS; dimerization is not required for nuclear localization, but MutLα is imported more efficiently than either monomer; the bipartite NLS of MLH1 can direct import of MutLα even when PMS2 NLS is mutated, providing redundant nuclear import mechanisms. Confocal microscopy in MMR-deficient cells, transient transfection of NLS mutants Molecular carcinogenesis Medium 19148896
2009 MLH1 and MBD4 cooperate in a mismatch repair pathway to signal apoptosis in Xenopus embryos depleted of xDNMT1; MBD4 interacts directly with both DNMT1 and MLH1, recruiting MLH1 to heterochromatic sites; depletion of xMLH1 increases survival of xDNMT1-depleted embryos, and MLH1/MBD4 accumulate at DNA damage sites in mammalian cells following micro-irradiation. Xenopus embryo depletion experiments, co-immunoprecipitation (MBD4-DNMT1-MLH1), live-cell micro-irradiation/time-lapse microscopy Development Medium 19502488
2009 HDAC6 interacts with and deacetylates MLH1 both in vitro and in vivo; deacetylation of MLH1 blocks assembly of the MutSα-MutLα complex; four acetylation sites in MLH1 were identified by MS; a deacetylation-mimetic MLH1 mutant confers resistance to 6-thioguanine, indicating that HDAC6-mediated deacetylation of MLH1 disrupts MMR complex formation and promotes DNA damage tolerance. Co-immunoprecipitation, in vitro deacetylation assay, mass spectrometry, site-directed mutagenesis, drug sensitivity assays The Journal of biological chemistry High 30770470
2010 MLH1 directly binds FANCJ (BACH1); an HNPCC-associated MLH1 L607H mutation ablates this interaction; FANCJ-deficient cells exhibit delayed MMR signaling and apoptotic responses to O6-methylguanine lesions, altering competition between MGMT-prosurvival and MMR-prodeath pathways; loss of FANCJ/MLH1 interaction sensitizes cells to DNA cross-linking agents. Co-immunoprecipitation, mutation analysis, cell survival and apoptosis assays Cancer prevention research Medium 20978114
2014 Saccharomyces cerevisiae Mlh1-Mlh3 (MutLγ) heterodimer is an endonuclease that nicks double-stranded DNA with marked preference for Holliday junctions (preferring the open unstacked form); human MLH1-MLH3 also shows preferential binding to Holliday junctions, establishing this as a conserved capacity of eukaryotic MutLγ distinct from all other eukaryotic MutL homologues. Purification of recombinant yeast and human Mlh1-Mlh3; in vitro endonuclease assay; DNA binding assays with Holliday junctions The Journal of biological chemistry High 24443562
2014 MLH1 deficiency causes reduction of SPTAN1 (non-erythroid spectrin αII) expression; siRNA knockdown of MLH1 decreases SPTAN1 mRNA levels; MLH1-deficient cells show impaired cellular motility, and overexpression of SPTAN1 rescues migration of MLH1-deficient cells, indicating MLH1 regulates cell migration via SPTAN1. siRNA knockdown, gene expression analysis, cell migration assays, SPTAN1 overexpression rescue Molecular cancer Medium 24456667
2018 MLH1 hMLH1 promoter mutation -42C>T (in a Myb binding site) reduces nuclear protein binding (EMSA) and reduces promoter-driven reporter expression to 37% of wild-type in transfection assays, demonstrating a heritable germline promoter mutation as a mechanism of partial loss of MLH1 function in HNPCC. Electrophoretic mobility shift assay (EMSA), reporter gene transfection assay Clinical genetics Medium 12919137
2020 Human MutLγ (MLH1-MLH3) is an endonuclease that nicks DNA; incision of covalently closed loop-containing DNA is promoted by MutSβ (MSH2-MSH3) and targeted to the strand opposite the loop; the resulting nick licenses downstream events leading to triplet repeat DNA expansion in human cell extracts. In vitro endonuclease assay with purified human MutLγ, MutSβ-stimulated nicking assay on loop substrates, cell extract expansion assay 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 in the presence of MutSγ; RFC and PCNA are additional components; PCNA interaction with MutLγ is required for meiotic crossover formation; the MutLγ-MutSγ-EXO1-RFC-PCNA ensemble preferentially cleaves DNA with Holliday junctions by nicking adjacent dsDNA rather than canonical resolvase activity. Biochemical reconstitution of pro-crossover nuclease ensemble; DNA cleavage assays; yeast genetics (PCNA interaction mutants showing crossover defects) Nature High 32814904
2020 Loss of MLH1 results in unrestrained DNA excision by Exonuclease 1 (Exo1) due to loss of MutLα-specific regulation of Exo1 during DNA repair; this leads to increased single-strand DNA formation, RPA exhaustion, DNA breaks, chromosomal abnormalities, and release of nuclear DNA into the cytoplasm, activating the cGAS-STING innate immune pathway. MLH1 knockout cell lines, Exo1 activity assays, ssDNA/RPA foci quantification, cytoplasmic DNA detection, cGAS-STING pathway reporter assays Cancer cell High 33338427
2000 MLH1 is part of BASC (BRCA1-associated genome surveillance complex), a large nuclear complex containing BRCA1, MSH2, MSH6, ATM, BLM, RAD50-MRE11-NBS1, and RFC/PCNA; BRCA1 and BLM colocalize with PCNA at large nuclear foci after agents that interfere with DNA synthesis, suggesting BASC serves as a sensor for DNA damage and replication-associated repair. Co-affinity purification, mass spectrometry, co-immunoprecipitation, immunofluorescence colocalization Genes & development Medium 10783165
2009 Hexavalent chromium [Cr(VI)] exposure increases H3K9 dimethylation at the MLH1 gene promoter via increased expression of G9a histone methyltransferase, leading to decreased MLH1 mRNA expression; ascorbate supplementation partially reverses this H3K9 dimethylation, implicating epigenetic silencing of MLH1 as a chromate carcinogenicity mechanism. ChIP for H3K9me2 at MLH1 promoter, qRT-PCR, Western blot for G9a, ascorbate rescue experiment Toxicology and applied pharmacology Medium 19376149
2003 MLH1 haploinsufficiency results in apoptotic resistance to alkylating agent MNU: Mgmt-/-/Mlh1+/- cells carrying ~half-normal MLH1 protein show no caspase-3 induction after MNU (unlike Mlh1+/+ cells), and mutant frequency increases 10-fold, demonstrating that MLH1 protein level is critical for determining cell fate (apoptosis vs. mutagenesis) after alkylation damage. Gene-targeted mouse cell lines (Mgmt/Mlh1 double mutants), cell survival assays, HPRT mutation frequency, caspase-3 Western blot DNA repair High 13679151
2018 MLH1 overexpression in endometrial carcinoma cells enhances sensitivity to cisplatin by activating the MLH1/c-Abl apoptosis signaling pathway involving c-Abl, caspase-9, caspase-3, and PARP; cisplatin-induced MLH1 upregulation correlates temporally with apoptosis induction; adenoviral MLH1 overexpression reduces xenograft tumor growth with cisplatin. siRNA knockdown, adenoviral overexpression, Western blot for c-Abl/caspase/PARP, flow cytometry for apoptosis, mouse xenograft model BMC cancer Medium 30594176
2024 Histone H3K9 lactylation (H3K9la) activates LUC7L2 transcription; LUC7L2 mediates intron 7 retention of MLH1, reducing MLH1 protein expression and inhibiting mismatch repair, ultimately leading to temozolomide resistance in glioblastoma; inhibiting lactate dehydrogenase A/B with stiripentol reverses H3K9la, restores MLH1 expression, and sensitizes GBM cells to temozolomide. CUT&Tag for H3K9la, SLAM-seq, RNA-seq, siRNA knockdown, Western blot, TMZ resistance assays in vitro and in vivo Advanced science Medium 38477507

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
1994 Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1881 8145827
1994 Mutation of a mutL homolog in hereditary colon cancer. Science (New York, N.Y.) 1737 8128251
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
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2002 E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes & development 957 11799067
2000 BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes & development 898 10783165
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2011 Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 836 21642682
1995 The molecular basis of Turcot's syndrome. The New England journal of medicine 770 7661930
1996 Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nature genetics 707 8673133
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 An empirical framework for binary interactome mapping. Nature methods 652 19060904
2006 Endonucleolytic function of MutLalpha in human mismatch repair. Cell 505 16873062
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
1996 Meiotic pachytene arrest in MLH1-deficient mice. Cell 483 8674118
2006 Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer research 471 16885385
1996 hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proceedings of the National Academy of Sciences of the United States of America 464 8942985
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1993 Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nature genetics 413 7903889
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2002 SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. Genes & development 398 11877377
2009 Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. British journal of cancer 397 19165197
2009 Risk of pancreatic cancer in families with Lynch syndrome. JAMA 396 19861671
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2004 Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database. Disease markers 347 15528792
2004 Germline epimutation of MLH1 in individuals with multiple cancers. Nature genetics 336 15064764
1994 MLH1, PMS1, and MSH2 interactions during the initiation of DNA mismatch repair in yeast. Science (New York, N.Y.) 291 8066446
1999 Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer research 204 9927033
2020 MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway. Cancer cell 196 33338427
2013 Cancer risks for MLH1 and MSH2 mutation carriers. Human mutation 195 23255516
2002 Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology 181 11781295
1999 Mutator phenotypes conferred by MLH1 overexpression and by heterozygosity for mlh1 mutations. Molecular and cellular biology 163 10082584
2005 Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology 162 16083711
2009 Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes, chromosomes & cancer 154 19455606
1997 Molecular basis of HNPCC: mutations of MMR genes. Human mutation 154 9259192
2005 HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology 144 15765394
1999 Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. Cancer research 140 10096563
2006 Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 137 17003395
2005 BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene 129 15782118
2024 Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2-Mediated MLH1 Intron Retention. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 124 38477507
2020 Regulation of the MLH1-MLH3 endonuclease in meiosis. Nature 115 32814904
2000 MSH4 acts in conjunction with MLH1 during mammalian meiosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 113 10928988
2009 Modulation of histone methylation and MLH1 gene silencing by hexavalent chromium. Toxicology and applied pharmacology 107 19376149
2002 Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Cancer investigation 96 11852992
2014 The Saccharomyces cerevisiae Mlh1-Mlh3 heterodimer is an endonuclease that preferentially binds to Holliday junctions. The Journal of biological chemistry 95 24443562
1997 Mutational analysis of MLH1 and MSH2 in 25 prospectively-acquired RER+ endometrial cancers. Genes, chromosomes & cancer 94 9071575
2002 Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. Genes, chromosomes & cancer 91 11793442
2001 Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors. Cancer 87 11753956
2017 A modifier of Huntington's disease onset at the MLH1 locus. Human molecular genetics 86 28934397
2003 Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 85 14512394
1996 Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer. American journal of human genetics 78 8940269
2006 Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. Human mutation 75 16395668
2005 Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Human genetics 75 16341550
2002 Suspected HNPCC and Amsterdam criteria II: evaluation of mutation detection rate, an international collaborative study. International journal of colorectal disease 71 12014418
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 68 32015124
2017 Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 68 28752838
2011 Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome. Journal of medical genetics 68 21712435
2014 Predictive value of CHFR and MLH1 methylation in human gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 66 24748501
2003 Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha. Molecular and cellular biology 65 12697830
2013 Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma. Oncotarget 61 24259277
2008 Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome. The Journal of pathology 58 17973250
2009 Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. Human mutation 56 19267393
2002 Contribution of human mlh1 and pms2 ATPase activities to DNA mismatch repair. The Journal of biological chemistry 55 11897781
2014 Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC). Journal of medical genetics 54 25280751
2013 Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Deutsches Arzteblatt international 53 23413378
2005 The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers. British journal of cancer 53 16106253
2001 Inactivation of DNA mismatch repair by increased expression of yeast MLH1. Molecular and cellular biology 49 11154280
2007 Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer. World journal of gastroenterology 48 17465465
2004 Challenges and pitfalls in HNPCC screening by microsatellite analysis and immunohistochemistry. The Journal of molecular diagnostics : JMD 47 15507669
2015 Relationship between MLH-1, MSH-2, PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer. International journal of clinical and experimental pathology 44 26097592
2002 Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation. Human mutation 43 12112654
2009 Clinical implications of microsatellite instability and MLH1 gene inactivation in sporadic insulinomas. The Journal of clinical endocrinology and metabolism 40 19567531
2003 Roles of MGMT and MLH1 proteins in alkylation-induced apoptosis and mutagenesis. DNA repair 39 13679151
2018 Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation. Cancer medicine 38 29341452
2003 Alterations in PMS2, MSH2 and MLH1 expression in human prostate cancer. International journal of oncology 38 12684669
2004 Identification of HNPCC by molecular analysis of colorectal and endometrial tumors. Disease markers 37 15528786
2004 Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. Human molecular genetics 37 15563510
2010 CHEK2 mutations and HNPCC-related colorectal cancer. International journal of cancer 36 19876921
2008 Functional analysis of HNPCC-related missense mutations in MSH2. Mutation research 36 18822302
2019 HDAC6 regulates DNA damage response via deacetylating MLH1. The Journal of biological chemistry 33 30770470
2013 Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. Clinical cancer research : an official journal of the American Association for Cancer Research 33 23403630
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2018 Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation. Journal of medical genetics 30 29472279
2007 Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma. Journal of medical genetics 29 17959715
2012 Vitamin and antioxidant rich diet increases MLH1 promoter DNA methylation in DMT2 subjects. Clinical epigenetics 28 23025454
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2009 MBD4 and MLH1 are required for apoptotic induction in xDNMT1-depleted embryos. Development (Cambridge, England) 28 19502488
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2009 Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice. The Journal of clinical investigation 26 19690386
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2004 Microsatellite instability and MLH1 promoter methylation in human retinoblastoma. Investigative ophthalmology & visual science 24 15452042
2010 Assessing the link between BACH1/FANCJ and MLH1 in DNA crosslink repair. Environmental and molecular mutagenesis 23 20658644
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2012 Functional characterization of MLH1 missense variants identified in Lynch syndrome patients. Human mutation 20 22753075
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2001 Optimization of experimental conditions for RNA-based sequencing of MLH1 and MSH2 genes. Human mutation 19 11139242
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