Disease relevance of ECs3688

• Evidence for a physical interaction between the Escherichia coli methyl-directed mismatch repair proteins MutL and UvrD [1].
• The Salmonella typhimurium and Escherichia coli MutS protein is one of several methyl-directed mismatch repair proteins that act together to correct replication errors [2].
• In Escherichia coli and related enteric bacteria, repair of base-base mismatches is performed by two overlapping biochemical processes, methyl-directed mismatch repair (MMR) and very short-patch (VSP) repair [3].
• Thus, the activity of the methyl-directed mismatch repair system is, at least in part, responsible for the low frequency of detectably heterozygous phage emerging from a standard cross [4].
• H. pylori gastritis is more frequent in patients with microsatellite instability-positive gastric cancers, and H. pylori organisms independently of inflammation can reduce DNA mismatch repair protein levels, raising the hypothesis that H. pylori organisms might lead to mutagenesis during infection [5].

High impact information on ECs3688

• Defects in methyl-directed mismatch repair underlie all mutator phenotypes described here [6].
• Screening of an E.coli genomic library revealed a potential interaction between UvrD and MutL, a component of the methyl-directed mismatch repair pathway [1].
• Escherichia coli methyl-directed mismatch repair is initiated by MutS-, MutL-, and ATP-dependent activation of MutH endonuclease, which cleaves at d(GATC) sites in the vicinity of a mismatch [7].
• A functional methyl-directed mismatch repair pathway in Escherichia coli prevents the formation of deletions between 101-bp tandem repeats with 4% sequence divergence [8].
• DNA helicase II is a well-characterized Escherichia coli enzyme capable of unwinding duplex DNA and known to be involved in both methyl-directed mismatch repair and excision repair of pyrimidine dimers [9].

Chemical compound and disease context of ECs3688

• Previous biochemical analysis of Escherichia coli methyl-directed mismatch repair implicates three redundant single-strand DNA-specific exonucleases (RecJ, ExoI, and ExoVII) and at least one additional unknown exonuclease in the excision reaction (Cooper, D. L., Lahue, R. S., and Modrich, P. (1993) J. Biol. Chem. 268, 11823-11829) [10].
• We wanted to establish whether strand breaks and gaps, arising during the removal of uracil from newly-synthesized DNA, can be utilized as strand discrimination signals by the methyl-directed mismatch repair system of Escherichia coli [11].
• Response of repair-competent and repair-deficient Escherichia coli to three O6-substituted guanines and involvement of methyl-directed mismatch repair in the processing of O6-methylguanine residues [12].
• Effects of high levels of DNA adenine methylation on methyl-directed mismatch repair in Escherichia coli [13].

Biological context of ECs3688

• Methyl-directed mismatch repair is a coordinated process that ensures replication fidelity and genome integrity by resolving base pair mismatches and insertion/deletion loops [14].
• MutL-catalyzed ATP hydrolysis is required at a post-UvrD loading step in methyl-directed mismatch repair [14].
• To evaluate the substrate specificity of methyl-directed mismatch repair in Escherichia coli extracts, we have constructed a set of DNA heteroduplexes, each of which contains one of the eight possible single base pair mismatches and a single hemimethylated d(GATC) site [15].
• This induction of the SOS response is not due to a defect in methyl-directed mismatch repair [16].
• We showed previously that mutations in methyl-directed mismatch repair of Escherichia coli reduced the occurrence of large deletions in (CTG.CAG)(175) repeats contained on plasmids [17].

Associations of ECs3688 with chemical compounds

• Our data show that the intermediates of uracil repair cannot substitute for the strand-discrimination signals generated by the MutH protein, which is thought to initiate the methyl-directed mismatch repair process by nicking the unmethylated strand of a newly-synthesized DNA duplex at d(GATC) sites [11].

Other interactions of ECs3688

• Misaligned structures that escape the exonuclease are repaired by the methyl-directed mismatch repair, albeit with limited efficiency [18].
• Enterobacterial GATC-specific DNA adenine methyltransferase (Dam) plays an essential role in regulation of DNA replication, methyl-directed mismatch repair, transposition and gene expression [19].

Analytical, diagnostic and therapeutic context of ECs3688

• Using electron microscopy and indirect end-labeling methods, we have examined excision tracts produced by the Escherichia coli methyl-directed mismatch repair system on a closed circular G-T heteroduplex that contains a single d(GATC) site [20].

References