DNA mismatch repair has a key role in maintaining genomic stability. Defects in mismatch repair cause elevated spontaneous mutation rates and increased instability of simple repetitive sequences, while mutations in human mismatch repair genes result in hereditary nonpolyposis colorectal cancers. Mismatch recognition represents the first critical step of mismatch repair. Genetic and biochemical ...

Mismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a "death conformation" of the MutS homologous proteins that is distinguishable from their "repair conformation." This conformation can be induced by a small molecule, reserpine, leading to DNA-independent cell death. We investigated the parameters for a small reserpine-like molecule ...

Insertion and deletion of small heteroduplex loops are common mutations in DNA, but why some loops are prone to mutation and others are efficiently repaired is unknown. Here we report that the mismatch recognition complex, MSH2/MSH3, discriminates between a repair-competent and a repair-resistant loop by sensing the conformational dynamics of their junctions. MSH2/MSH3 binds, bends, and dissoci...

Alterations in trinucleotide repeat length during transmission are important in the pathophysiology of Huntington's disease (HD). However, it is not well understood where, when and by what mechanism expansion occurs. We have followed the fate of CAG repeats during development in mice that can [hHD(-/+)/Msh2(+/+)] or cannot [hHD(-/+)/Msh2(-/-)] expand their repeats. Here we show that long repeat...

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition syndrome caused by germ line mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2, with large genomic rearrangements accounting for 5% to 20% of all mutations. Although crucial to the understanding of cancer initiation, little is known about the second, somatic hit in HNPC...

The yeast Saccharomyces cerevisiae encodes a set of genes that show strong amino acid sequence similarity to MutS and MutL, proteins required for mismatch repair in Escherichia coli. 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. By using specifically marked HIS4 and ARG4 alleles, w...

Background: Though the incidence of colorectal carcinoma (CRC) is relatively uncommon in Nigeria, compared to the developed countries, recent studies indicate an increasing trend. Our patients often present at an earlier age, which has important implications for the pathogenesis in Nigeria. MLH1, MSH2, MSH6, PMS2 are the commonly mutated MMR genes in descending order of frequency, with PMS1 and...

BACKGROUND The human Mut-S-homolog-2 (MSH2) is part of the DNA mismatch repair system (MMR). Mutations in genes of the MMR are a predisposition to hereditary non-polyposis colorectal cancer (HNPCC). In women, MMR gene mutations may lead to primary endometrial cancer (EC). The important function of the MMR for the integrity of the DNA during replication makes it probable that the MMR might also ...

Although the primary function of the DNA mismatch repair (MMR) system is to identify and correct base mismatches that have been erroneously introduced during DNA replication, recent studies have further implicated several MMR components in somatic hypermutation of immunoglobulin (Ig) genes. We studied the immune response in mice deficient in MutS homologue (MSH)3 and MSH6, two mutually exclusiv...