MLH1/YMR167W Summary Help

Standard Name MLH1 1
Systematic Name YMR167W
Alias PMS2 2
Feature Type ORF, Verified
Description Protein required for mismatch repair in mitosis and meiosis; also required for crossing over during meiosis; forms a complex with Pms1p and Msh2p-Msh3p during mismatch repair; human homolog is associated with hereditary non-polyposis colon cancer (1, 3, 4, 5 and see Summary Paragraph)
Name Description MutL Homolog 1
Chromosomal Location
ChrXIII:594886 to 597195 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All MLH1 GO evidence and references
  View Computational GO annotations for MLH1
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
High-throughput
Regulators 4 genes
Resources
Classical genetics
null
overexpression
reduction of function
unspecified
Large-scale survey
null
overexpression
unspecified
Resources
208 total interaction(s) for 95 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 15
  • Affinity Capture-Western: 7
  • Co-crystal Structure: 3
  • Co-purification: 11
  • PCA: 1
  • Protein-peptide: 3
  • Reconstituted Complex: 22
  • Two-hybrid: 33

Genetic Interactions
  • Dosage Growth Defect: 1
  • Dosage Rescue: 2
  • Negative Genetic: 34
  • Phenotypic Enhancement: 20
  • Phenotypic Suppression: 4
  • Positive Genetic: 42
  • Synthetic Growth Defect: 5
  • Synthetic Lethality: 5

Resources
Expression Summary
histogram
Resources
Length (a.a.) 769
Molecular Weight (Da) 87,061
Isoelectric Point (pI) 6.93
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXIII:594886 to 597195 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..2310 594886..597195 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000004777
SUMMARY PARAGRAPH for MLH1

MLH1, one of four MutL homologs in S. cerevisiae, is involved in mismatch repair during mitosis and meiosis and plays a role separate from its mismatch repair functions in crossing-over during meiotic recombination (reviewed in 6, 7). Mlh1p is involved in the repair of mismatches caused by errors during replication (1) as well as the repair of DNA damage caused by cisplatin, alkylating agents, and oxidation (8). Mlh1p is also involved in the correction of mismatches that arise during the formation of heteroduplex DNA between two homologous chromosomes during meiotic recombination. Failure to repair these mismatches during meiosis leads to an increase of post-meiotic segregation (PMS) events in which the 4:4 Mendelian segregation pattern of the 8 single-strands of DNA is altered to a 5:3 non-Mendelian segregation pattern. Consistent with its multiple roles in mismatch repair, an mlh1 mutant displays a severe mutator phenotype as well as an increase in PMS events (2, 9). An increase in Mlh1p levels also displays a mutator phenotype (10). In addition to its role in mismatch repair, Mlh1p has been proposed to be involved in regulating the total level, types, and resolution of heteroduplexes during meiotic crossing-over (11, 12, 5, and references within).

The functional specificity of Mlh1p may result from its interaction with each of the three other MutL homologs (13, 14, 15, 16). The Mlh1p-Pms1p heterodimer plays a major role in mismatch repair but a limited role in meiotic crossing-over. Although the Mlh1p-Pms1p heterodimer does not bind mismatched DNA, it interacts with both Msh2p-Msh3p and Msh2-Msh6p heterodimers during mismatch repair (4, 17). A pms1 mutant exhibits a severe mutator phenotype and increased PMS events but normal levels of crossing-over (9, 1, 16). In contrast to the Mlh1p-Pms1p heterodimer, Mlh1p-Mlh2p and Mlh1p-Mlh3p heterodimers play smaller roles in general mismatch repair and larger roles in the resolution of heteroduplexes formed during meiotic recombination. The Mlh1p-Mlh2p and Mlh1p-Mlh3p heterodimers are involved in the repair of specific types of mismatches (15, 18). Both mlh2 and mlh3 single mutants display defects in both the levels and types of cross-over events observed during meiosis (16). An mlh3 mutant displays a reduced level of crossing-over during meiosis similar to an mlh1 single mutant, an msh4 single mutant, and an mlh1 msh4 double mutant, suggesting that the Mlh1p-Mlh3p heterodimer may interact with the Msh4p-Msh5p heterodimer to regulate cross-overs (19).

Transcription of MLH1 does not appear to be regulated during the mitotic and meiotic cell cycles (20, 21).

Mlh1p is similar to the bacterial MutL and HexB mismatch repair proteins and the human hMLH1 protein (OMIM) responsible for hereditary non-polyposis colorectal cancer (HNPCC) (OMIM) (9, 3). Mutating MLH1 at positions analogous to those observed to be associated with HNPCC in humans with mutated hMLH1 results in a mutator phenotype in yeast (22).

Last updated: 2007-04-17 Contact SGD

References cited on this page View Complete Literature Guide for MLH1
1) Strand M, et al.  (1993) Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365(6443):274-6
2) Kramer B, et al.  (1989) Heteroduplex DNA correction in Saccharomyces cerevisiae is mismatch specific and requires functional PMS genes. Mol Cell Biol 9(10):4432-40
3) Bronner CE, et al.  (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368(6468):258-61
4) Habraken Y, et al.  (1997) Enhancement of MSH2-MSH3-mediated mismatch recognition by the yeast MLH1-PMS1 complex. Curr Biol 7(10):790-3
5) Argueso JL, et al.  (2003) Systematic mutagenesis of the Saccharomyces cerevisiae MLH1 gene reveals distinct roles for Mlh1p in meiotic crossing over and in vegetative and meiotic mismatch repair. Mol Cell Biol 23(3):873-86
6) Kolodner RD and Marsischky GT  (1999) Eukaryotic DNA mismatch repair. Curr Opin Genet Dev 9(1):89-96
7) Borts RH, et al.  (2000) The many faces of mismatch repair in meiosis. Mutat Res 451(1-2):129-50
8) Simon JA, et al.  (2000) Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae. Cancer Res 60(2):328-33
9) Prolla TA, et al.  (1994) Dual requirement in yeast DNA mismatch repair for MLH1 and PMS1, two homologs of the bacterial mutL gene. Mol Cell Biol 14(1):407-15
10) Shcherbakova PV, et al.  (2001) Inactivation of DNA mismatch repair by increased expression of yeast MLH1. Mol Cell Biol 21(3):940-51
11) Hoffmann ER, et al.  (2005) MLH1 and MSH2 promote the symmetry of double-strand break repair events at the HIS4 hotspot in Saccharomyces cerevisiae. Genetics 169(3):1291-303
12) Argueso JL, et al.  (2004) Competing crossover pathways act during meiosis in Saccharomyces cerevisiae. Genetics 168(4):1805-16
13) Prolla TA, et al.  (1994) MLH1, PMS1, and MSH2 interactions during the initiation of DNA mismatch repair in yeast. Science 265(5175):1091-3
14) Pang Q, et al.  (1997) Functional domains of the Saccharomyces cerevisiae Mlh1p and Pms1p DNA mismatch repair proteins and their relevance to human hereditary nonpolyposis colorectal cancer-associated mutations. Mol Cell Biol 17(8):4465-73
15) Flores-Rozas H and Kolodner RD  (1998) The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations. Proc Natl Acad Sci U S A 95(21):12404-9
16) Wang TF, et al.  (1999) Functional specificity of MutL homologs in yeast: evidence for three Mlh1-based heterocomplexes with distinct roles during meiosis in recombination and mismatch correction. Proc Natl Acad Sci U S A 96(24):13914-9
17) Habraken Y, et al.  (1998) ATP-dependent assembly of a ternary complex consisting of a DNA mismatch and the yeast MSH2-MSH6 and MLH1-PMS1 protein complexes. J Biol Chem 273(16):9837-41
18) Harfe BD, et al.  (2000) Discrete in vivo roles for the MutL homologs Mlh2p and Mlh3p in the removal of frameshift intermediates in budding yeast. Curr Biol 10(3):145-8
19) Hunter N and Borts RH  (1997) Mlh1 is unique among mismatch repair proteins in its ability to promote crossing-over during meiosis. Genes Dev 11(12):1573-82
20) Kramer W, et al.  (1996) Transcription of mutS and mutL-homologous genes in Saccharomyces cerevisiae during the cell cycle. Mol Gen Genet 252(3):275-83
21) Meyer C, et al.  (2001) Transcription of mutS- and mutL-homologous genes during meiosis in Saccharomyces cerevisiae and identification of a regulatory cis-element for meiotic induction of MSH2. Mol Genet Genomics 265(5):826-36
22) Hoffmann ER, et al.  (2003) MLH1 mutations differentially affect meiotic functions in Saccharomyces cerevisiae. Genetics 163(2):515-26