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Protein

DNA mismatch repair protein Mlh1

Gene

MLH1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.5 Publications

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Cell cycle, DNA damage, DNA repair

Enzyme and pathway databases

ReactomeiR-HSA-5358565. Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
R-HSA-5358606. Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta).
R-HSA-6796648. TP53 Regulates Transcription of DNA Repair Genes.
R-HSA-912446. Meiotic recombination.

Names & Taxonomyi

Protein namesi
Recommended name:
DNA mismatch repair protein Mlh1
Alternative name(s):
MutL protein homolog 1
Gene namesi
Name:MLH1
Synonyms:COCA2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:7127. MLH1.

Subcellular locationi

GO - Cellular componenti

  • chiasma Source: GO_Central
  • male germ cell nucleus Source: Ensembl
  • membrane Source: UniProtKB
  • MutLalpha complex Source: GO_Central
  • nucleoplasm Source: HPA
  • nucleus Source: HGNC
  • synaptonemal complex Source: GO_Central
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Hereditary non-polyposis colorectal cancer 2 (HNPCC2)58 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected.
See also OMIM:609310
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti18 – 181R → C in HNPCC2. 1 Publication
VAR_022663
Natural varianti19 – 191I → F in HNPCC2; unknown pathological significance. 1 Publication
VAR_043383
Natural varianti21 – 211A → V in HNPCC2. 1 Publication
VAR_043384
Natural varianti25 – 251I → F in HNPCC2. 1 Publication
VAR_043385
Natural varianti28 – 281P → L in HNPCC2; loss of protein expression; normal interaction with PMS2 and EXO1; decreased mismatch repair activity; no effect on nuclear localization. 7 Publications
VAR_004433
Natural varianti29 – 291A → S in HNPCC2; unknown pathological significance; acts functionally like the wild-type protein. 3 Publications
VAR_043386
Natural varianti31 – 311A → C in HNPCC2; requires 2 nucleotide substitutions; decreased mismatch repair activity. 1 Publication
VAR_076338
Natural varianti35 – 351M → K in HNPCC2; unknown pathological significance. 1 Publication
VAR_043387
Natural varianti35 – 351M → R in HNPCC2.
VAR_004434
Natural varianti37 – 371E → K in HNPCC2; decreased mismatch repair activity; loss of nuclear localization. 2 Publications
VAR_076339
Natural varianti38 – 381N → H in HNPCC2; decreased mismatch repair activity; no effect on nuclear localization. 3 Publications
VAR_043389
Natural varianti38 – 381N → K in HNPCC2; decreased mismatch repair activity; no effect on nuclear localization. 2 Publications
VAR_076340
Natural varianti41 – 411D → G in HNPCC2. 1 Publication
VAR_043390
Natural varianti41 – 411D → H Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054522
Natural varianti44 – 441S → F in HNPCC2; no effect on MLH1 splicing; loss of mismatch repair activity. 3 Publications
VAR_004436
Natural varianti45 – 473TSI → CF in HNPCC2; decreased mismatch repair activity; loss of protein expression; loss of nuclear localization. 1 Publication
VAR_043391
Natural varianti62 – 621Q → K in HNPCC2; decreased mismatch repair activity. 1 Publication
VAR_004437
Natural varianti63 – 631D → E in HNPCC2; decreased mismatch repair activity; loss of protein expression; loss of nuclear localization. 2 Publications
VAR_043392
Natural varianti64 – 641N → S in HNPCC2. 1 Publication
VAR_004438
Natural varianti67 – 671G → R in HNPCC2; no effect on MLH1 splicing; decreased mismatch repair activity; loss of protein expression; loss of nuclear localization. 11 Publications
VAR_004439
Natural varianti67 – 671G → W in HNPCC2. 2 Publications
VAR_012903
Natural varianti68 – 681I → N in HNPCC2; decreased mismatch repair activity. 1 Publication
VAR_004440
Natural varianti69 – 691R → K in HNPCC2; decreased mismatch repair activity. 1 Publication
VAR_004441
Natural varianti71 – 711Missing in HNPCC2; decreased mismatch repair activity; loss of protein expression. 2 Publications
VAR_043393
Natural varianti77 – 771C → R in HNPCC2 and CRC; sporadic; decreased mismatch repair activity; loss of nuclear localization; normal interaction with PMS2. 5 Publications
VAR_004442
Natural varianti80 – 801F → V in HNPCC2; decreased mismatch repair activity. 3 Publications
VAR_012905
Natural varianti84 – 841K → E in HNPCC2; decreased mismatch repair activity. 3 Publications
VAR_012906
Natural varianti98 – 981G → S Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054523
Natural varianti101 – 1011G → D in HNPCC2; no effect on MLH1 splicing. 2 Publications
VAR_022664
Natural varianti101 – 1011G → S Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054524
Natural varianti102 – 1021E → K in HNPCC2; unknown pathological significance. 1 Publication
VAR_043394
Natural varianti107 – 1071I → R in HNPCC2; decreased mismatch repair activity; normal interaction with PMS2; loss of protein expression; loss of nuclear localization. 3 Publications
VAR_004444
Natural varianti109 – 1091H → P in HNPCC2; decreased mismatch repair activity; no effect on nuclear localization. 2 Publications
VAR_076341
Natural varianti111 – 1111A → P in HNPCC2; decreased mismatch repair activity. 2 Publications
VAR_076342
Natural varianti111 – 1111A → V in HNPCC2; unknown pathological significance. 2 Publications
VAR_012907
Natural varianti116 – 1161T → K Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054525
Natural varianti117 – 1171T → M in HNPCC2; decreased mismatch repair activity; no effect on MLH1 splicing; fails to interact with PMS2 and EXO1; loss of nuclear localization. 11 Publications
VAR_004445
Natural varianti117 – 1171T → R in HNPCC2; decreased mismatch repair activity. 1 Publication
VAR_004446
Natural varianti126 – 1261Y → N Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
Corresponds to variant rs200076893 [ dbSNP | Ensembl ].
VAR_054526
Natural varianti128 – 1281A → P in HNPCC2. 1 Publication
VAR_012908
Natural varianti155 – 1551L → R in HNPCC2; decreased mismatch repair activity; loss of protein expression; loss of nuclear localization. 2 Publications
VAR_043397
Natural varianti182 – 1821R → G in HNPCC2; incomplete. 2 Publications
VAR_012909
Natural varianti182 – 1821R → K in HNPCC2. 1 Publication
VAR_022666
Natural varianti185 – 1851V → G in HNPCC2; decreased mismatch repair activity; loss of protein expression; loss of nuclear localization; no effect on MLH1 splicing. 3 Publications
VAR_004447
Natural varianti185 – 1851V → L in HNPCC2; unknown pathological significance. 1 Publication
VAR_043398
Natural varianti193 – 1931S → P in HNPCC2. 1 Publication
VAR_004448
Natural varianti215 – 2151N → S Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054527
Natural varianti216 – 2161I → S Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054528
Natural varianti217 – 2171R → C in HNPCC2; unknown pathological significance; no decrease in mismatch repair activity. 4 Publications
Corresponds to variant rs4986984 [ dbSNP | Ensembl ].
VAR_004449
Natural varianti226 – 29570Missing in HNPCC2.
VAR_004452Add
BLAST
Natural varianti226 – 2261R → L in HNPCC2. 1 Publication
VAR_004451
Natural varianti233 – 2331Missing in HNPCC2; loss of nuclear localization. 1 Publication
VAR_076343
Natural varianti234 – 2341E → G in HNPCC2; unknown pathological significance. 1 Publication
VAR_043399
Natural varianti244 – 2441G → D in HNPCC2; decreased mismatch repair activity. 3 Publications
VAR_012911
Natural varianti247 – 2471S → P in HNPCC2; decreased mismatch repair activity; loss of protein expression; loss of nuclear localization. 3 Publications
VAR_043400
Natural varianti260 – 2601L → F Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054529
Natural varianti262 – 2621Missing in HNPCC2. 1 Publication
VAR_012913
Natural varianti264 – 2641H → Y in HNPCC2. 1 Publication
VAR_043402
Natural varianti265 – 2651R → C in HNPCC2; results in partial MLH1 exon 10 skipping on ex vivo splicing assay; decreased mismatch repair activity; no effect on nuclear localization. 3 Publications
VAR_054530
Natural varianti265 – 2651R → H Rare polymorphism; associated with HNPCC2; results in partial MLH1 exon 10 skipping on ex vivo splicing assay; decreased mismatch repair activity. 4 Publications
VAR_012914
Natural varianti265 – 2651R → S in HNPCC2; decreased mismatch repair activity. 1 Publication
VAR_076344
Natural varianti282 – 2821A → G in HNPCC2. 1 Publication
VAR_043403
Natural varianti292 – 2921L → P in HNPCC2; unknown pathological significance. 2 Publications
VAR_043404
Natural varianti295 – 2951S → T in HNPCC2. 1 Publication
VAR_012916
Natural varianti304 – 3041D → V in HNPCC2. 1 Publication
VAR_043405
Natural varianti320 – 3201E → D Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054531
Natural varianti321 – 3211S → I in HNPCC2; unknown pathological significance. 1 Publication
VAR_043406
Natural varianti326 – 3261V → A in HNPCC2; no decrease in mismatch repair activity. 3 Publications
Corresponds to variant rs63751049 [ dbSNP | Ensembl ].
VAR_004453
Natural varianti329 – 3291H → P in HNPCC2; loss of protein expression; loss of nuclear localization. 5 Publications
VAR_012918
Natural varianti330 – 3301Missing in HNPCC2; results in weak MLH1 exon 11 skipping on ex vivo splicing assay; decreased mismatch repair activity; loss of protein expression; loss of nuclear localization. 3 Publications
VAR_043408
Natural varianti338 – 3381N → S in HNPCC2. 1 Publication
VAR_043409
Natural varianti379 – 3791Y → C in HNPCC2. 1 Publication
VAR_022667
Natural varianti385 – 3851R → C in HNPCC2; unknown pathological significance. 1 Publication
VAR_043410
Natural varianti385 – 3851R → P in HNPCC2; unknown pathological significance. 1 Publication
VAR_043411
Natural varianti389 – 3891R → W in HNPCC2; unknown pathological significance; no effect on nuclear localization; normal interaction with PMS2 and EXO1. 1 Publication
VAR_076345
Natural varianti441 – 4411A → T in HNPCC2. 2 Publications
VAR_012920
Natural varianti443 – 4431K → Q in HNPCC2; unknown pathological significance; no decrease in mismatch repair activity; no effect on nuclear localization. 4 Publications
Corresponds to variant rs34213726 [ dbSNP | Ensembl ].
VAR_043412
Natural varianti460 – 4601E → A in HNPCC2; unknown pathological significance. 1 Publication
VAR_076347
Natural varianti474 – 4741R → Q in HNPCC2; unknown pathological significance. 2 Publications
VAR_043414
Natural varianti474 – 4741R → W Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054532
Natural varianti485 – 4851D → E in HNPCC2. 1 Publication
VAR_043415
Natural varianti485 – 4851D → H in HNPCC2; unknown pathological significance. 1 Publication
VAR_043416
Natural varianti492 – 4921A → T in HNPCC2; also found in sporadic colorectal cancer. 1 Publication
VAR_004455
Natural varianti506 – 5061V → A in HNPCC2.
VAR_004456
Natural varianti539 – 5391A → D Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054533
Natural varianti542 – 5421Q → L in HNPCC2; type II; decreased mismatch repair activity. 3 Publications
VAR_004457
Natural varianti542 – 5421Q → P in HNPCC2. 1 Publication
VAR_043417
Natural varianti549 – 5491L → P in HNPCC2; no effect on MLH1 splicing. 3 Publications
VAR_012921
Natural varianti550 – 5501L → P in HNPCC2; decreased mismatch repair activity; defective in interaction with PMS2 and EXO1; loss of protein expression; may lose nuclear localization. 4 Publications
VAR_043418
Natural varianti551 – 5511N → T in HNPCC2; no effect on MLH1 splicing. 3 Publications
VAR_012922
Natural varianti559 – 5591L → R in HNPCC2. 1 Publication
VAR_022668
Natural varianti565 – 5651I → F in HNPCC2. 1 Publication
VAR_012923
Natural varianti574 – 5741L → P in HNPCC2; type I; abrogates interaction with EXO1. 4 Publications
VAR_004458
Natural varianti578 – 63255Missing in HNPCC2; decreased mismatch repair activity; defective in interaction with PMS2. 1 Publication
VAR_076348Add
BLAST
Natural varianti578 – 5781E → G in HNPCC2 and CRC; unknown pathological significance; no decrease in mismatch repair activity; no effect on nuclear localization. 3 Publications
VAR_004459
Natural varianti582 – 5821L → F in HNPCC2; decreased mismatch repair activity; no effect on nuclear localization. 2 Publications
VAR_076349
Natural varianti582 – 5821L → V in HNPCC2; type II. 1 Publication
Corresponds to variant rs63751713 [ dbSNP | Ensembl ].
VAR_004460
Natural varianti585 – 5851L → R Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054534
Natural varianti586 – 5861A → P in HNPCC2. 1 Publication
VAR_015689
Natural varianti588 – 5881L → P in HNPCC2. 1 Publication
VAR_012924
Natural varianti589 – 5891A → D in HNPCC2; decreased mismatch repair activity; loss of interaction with PMS2 and EXO1; loss of protein expression; may lose nuclear localization. 4 Publications
VAR_043419
Natural varianti596 – 5961Missing in HNPCC2.
VAR_043420
Natural varianti603 – 6031P → R in HNPCC2; unknown pathological significance; no effect on MLH1 splicing. 3 Publications
Corresponds to variant rs35831931 [ dbSNP | Ensembl ].
VAR_012925
Natural varianti607 – 6071L → H in HNPCC2; unknown pathological significance; also found in lobular carcinoma in situ of the breast; no effect on MLH1 splicing. 5 Publications
Corresponds to variant rs41295284 [ dbSNP | Ensembl ].
VAR_012926
Natural varianti612 – 6121Missing in HNPCC2; loss of protein expression; loss of nuclear localization. 2 Publications
VAR_043422
Natural varianti616 – 6161Missing in HNPCC2 and MMRCS; abrogates interaction with EXO1; loss of protein expression; loss of nuclear localization; no effect on MLH1 splicing. 11 Publications
VAR_004461
Natural varianti618 – 6181K → A in HNPCC2; unknown pathological significance; requires 2 nucleotide substitutions; interacts weakly with PMS2; no decrease in mismatch repair activity; no effect on nuclear localization. 12 Publications
Corresponds to variant rs35502531 [ dbSNP | Ensembl ].
VAR_004462
Natural varianti618 – 6181K → T in HNPCC2; type II; loss of nuclear localization. 7 Publications
VAR_004463
Natural varianti618 – 6181Missing in HNPCC2. 1 Publication
VAR_043423
Natural varianti619 – 6191A → P Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054535
Natural varianti622 – 6221L → H in HNPCC2. 1 Publication
VAR_012927
Natural varianti623 – 6231A → P in HNPCC2; unknown pathological significance. 1 Publication
VAR_043425
Natural varianti626 – 6272FS → ST in HNPCC2.
VAR_004464
Natural varianti631 – 6311D → A in HNPCC2; unknown pathological significance. 1 Publication
VAR_043426
Natural varianti633 – 66331Missing in HNPCC2; decreased mismatch repair activity; defective in interaction with PMS2; loss of protein expression; loss of nuclear localization. 1 Publication
VAR_076350Add
BLAST
Natural varianti636 – 6361L → P in HNPCC2. 1 Publication
VAR_043428
Natural varianti640 – 6401P → L Associated with HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054536
Natural varianti640 – 6401P → S in HNPCC2; no effect on MLH1 splicing. 2 Publications
VAR_043429
Natural varianti646 – 6461Y → C in HNPCC2; defective in interaction with PMS2 and EXO1; no decrease in mismatch repair activity. 5 Publications
Corresponds to variant rs35045067 [ dbSNP | Ensembl ].
VAR_043430
Natural varianti648 – 6481P → L in HNPCC2; unknown pathological significance; defective in interaction with PMS2 and EXO1; may lose nuclear localization; loss of protein expression; no decrease in mismatch repair activity. 5 Publications
VAR_012928
Natural varianti648 – 6481P → S in HNPCC2; the protein is unstable; loss of nuclear localization; loss of protein expression; no decrease in mismatch repair activity. 4 Publications
VAR_022669
Natural varianti654 – 6541P → L in HNPCC2; decreased mismatch repair activity; defective in interaction with PMS2 and EXO1; loss of protein expression; may lose nuclear localization. 4 Publications
VAR_043431
Natural varianti655 – 6551I → V in HNPCC2; also found in an endometrial cancer sample; no effect on MLH1 splicing. 2 Publications
Corresponds to variant rs55907433 [ dbSNP | Ensembl ].
VAR_043432
Natural varianti656 – 6561F → S in HNPCC2; no effect on MLH1 splicing. 1 Publication
VAR_054537
Natural varianti657 – 6571Missing in HNPCC2; unknown pathological significance. 1 Publication
VAR_043433
Natural varianti659 – 6591R → L in HNPCC2. 2 Publications
VAR_012929
Natural varianti659 – 6591R → P in HNPCC2; interacts only very weakly with PMS2; abrogates interaction with EXO1; decreased mismatch repair activity; may lose nuclear localization. 6 Publications
VAR_004465
Natural varianti659 – 6591R → Q in HNPCC2; unknown pathological significance. 2 Publications
VAR_043434
Natural varianti662 – 6621T → P in HNPCC2; unknown pathological significance. 2 Publications
VAR_012930
Natural varianti666 – 6661W → R in HNPCC2; unknown pathological significance; no effect on MLH1 splicing. 1 Publication
VAR_054538
Natural varianti681 – 6811A → T in HNPCC2; unknown pathological significance; abrogates interaction with EXO1; no decrease in mismatch repair activity. 7 Publications
VAR_004466
Natural varianti687 – 6871R → W in HNPCC2; unknown pathological significance. 4 Publications
VAR_012931
Natural varianti718 – 7181H → Y in HNPCC2; unknown pathological significance. 3 Publications
Corresponds to variant rs2020873 [ dbSNP | Ensembl ].
VAR_004467
Natural varianti719 – 7191I → INVFHI in HNPCC2.
VAR_043435
Natural varianti724 – 7241L → M in HNPCC2. 1 Publication
VAR_043436
Natural varianti751 – 7511K → R in HNPCC2; unknown pathological significance. 3 Publications