Disease relevance of PMS1

• We propose that the POL3 3'-->5' exonuclease and the PMS1 mismatch repair system act on a common pathway analogous to the dnaQ-->mutHLS pathway of DNA replication error correction in Escherichia coli [1].
• Using site-directed mutagenesis, we altered a number of highly conserved residues in the Mlh1p and Pms1p proteins, including some alterations that mimic germline mutations observed for human hereditary nonpolyposis colorectal cancer [2].
• Nucleotide sequence of the Salmonella typhimurium mutL gene required for mismatch repair: homology of MutL to HexB of Streptococcus pneumoniae and to PMS1 of the yeast Saccharomyces cerevisiae [3].

High impact information on PMS1

• We show here that mutations in any three yeast genes involved in DNA mismatch repair (PMS1, MLH1 and MSH2) lead to 100- to 700-fold increases in tract instability, whereas mutations that eliminate the proof-reading function of DNA polymerases have little effect [4].
• We have studied the correction of heteroduplex plasmid DNA in pms1 mutant strains of Saccharomyces cerevisiae, which are known to exhibit higher frequencies of 5:3 type tetrads and lower frequencies of 6:2 tetrads than wild-type strains [5].
• Our results suggest that the pms1 mutation causes a defect in mismatch correction, supporting the hypothesis that meiotic gene conversion in wild-type yeast cells often results from the correction of heteroduplex DNA [5].
• MLH1, PMS1, and MSH2 interactions during the initiation of DNA mismatch repair in yeast [6].
• A pol3-01/pol3-01 pms1/pms1 diploid was viable and displayed an estimated URA3 relative mutation rate of 2 x 10(4), which we calculate to be catastrophically high in a haploid [1].

Biological context of PMS1

• Mutations in the yeast DNA mismatch repair genes MSH2, PMS1, and MLH1 increase the frequency of mutations for normal DNA sequences and destabilize microsatellites [7].
• We examined the role of MSH2 and PMS1, yeast homologs of mutS and mutL, respectively, in the repair of base pair mismatches formed during meiotic recombination [8].
• Both reduced and increased expression of PMS1 resulted in a mitotic mutator phenotype [9].
• Regulation of the PMS1 gene was dependent on intact MluI cell cycle boxes, as demonstrated by analysis of a promoter mutant [9].
• We found that all mutS homologues (MSH1-6) were induced during meiosis, whereas no evidence for regulation of the mutL homologues (PMS1, MLH1-3) was obtained [10].

Anatomical context of PMS1

• Analysis of yeast pms1, msh2, and mlh1 mutators points to differences in mismatch correction efficiencies between prokaryotic and eukaryotic cells [11].

Associations of PMS1 with chemical compounds

• The MLH1-PMS1 heterodimer then interacts with the MSH proteins at or near the mismatch site and is thought to act as a mediator to recruit downstream repair proteins [12].
• Additionally, the NH2 end coding region of PMS1 is found in the 3' end of the sequence [13].
• Interestingly, double mutants in the MLH1 and PMS1 genes were deficient in TCR of thymine glycols [14].
• Furthermore, two-hybrid analysis suggested that these ATP-binding-induced conformational changes promote an interaction between the NH(2) termini of Mlh1p and Pms1p [15].
• Mlh1-Pms1 also binds to DNA, but independently of a mismatch [16].

Physical interactions of PMS1

• Three approaches, ATP hydrolysis assays, limited proteolysis protection, and equilibrium dialysis, provide evidence that the amino-terminal domain of Mlh1 binds ATP with >10-fold higher affinity than does the amino-terminal domain of Pms1 [17].
• We propose that the inhibition of conversion by large inserts is due to recognition by the Msh2/Pms1 complex of mismatches created by intrastrand interactions in the heteroduplex loop [18].

Regulatory relationships of PMS1

• Overexpression of the PMS1 gene alone caused a moderate increase in the mutation rate and strongly suppressed the mutator effect caused by MLH1 overexpression [19].
• The hsm3 mutation suppressed synthetic lethality in the hsm3 pol3-01 pms1 triple mutant and dramatically increased the spontaneous mutation rate in comparison with double mutant [20].
• In contrast to their similar antimutator roles, Pms1p consistently inhibited recombination to a lesser degree than did Msh2p [21].

Other interactions of PMS1

• Of these, MLH1 and PMS1 are known to act in the MSH2-dependent pathway that repairs DNA mismatches [22].
• The mismatch repair mutations pms1, msh2 and msh3 did not affect 31- and 61-bp deletions in the pol3-t but increased the rates of 7- and 1-bp deletions [23].
• In contrast to the pol3-t, the enhancement of 1-bp deletions in a rad52 mutant is not altered by a pms1 mutation [23].
• Epistasis analysis of double mutants shows that the PMS1 and HSM3 genes control different mismatch repair systems [24].
• Mismatch repair proteins Msh6, Pms1, and Mlh1 are not required [25].

Analytical, diagnostic and therapeutic context of PMS1

• Here, we utilized both genetic and surface plasmon resonance techniques to characterize the MLH1-PMS1-PCNA interaction [26].
• The two domains are sufficient for Mlh1p-Pms1p interaction, as determined by the two-hybrid assay and by in vitro protein affinity chromatography [2].
• Analytical ultracentrifugation experiments showed that purified Mlh1p forms a homodimer in solution, albeit with a K(d) of 3.14 microM, 36-fold higher than that for Mlh1p-Pms1p heterodimerization [19].
• Cooperative binding was observed visually by atomic force microscopy as long, continuous tracts of Mlh1-Pms1 protein bound to duplex DNA [27].
• Complementation tests were performed by crossing all seven new mutant isolates to pms1 and pms2 mutants and assaying for mutant phenotype in the diploids [28].

References