Sequence-dependent effect of interruptions on microsatellite mutation rate in mismatch repair-deficient human cells.

Although microsatellite mutation rates generally increase with increasing length of the repeat tract, interruptions in a microsatellite may stabilize it. We have performed a direct analysis of the effect of microsatellite interruptions on mutation rate and spectrum in cultured mammalian cells. Two mononucleotide sequences (G(17) and A(17)) and a dinucleotide [(CA)(17)] were compared with interrupted repeats of the same size and with sequences of 8 repeat units.

Ninety-six haploid yeast strains with individual disruptions of open reading frames between YOR097C and YOR192C, constructed for the Saccharomyces genome deletion project, have an additional mutation in the mismatch repair gene MSH3.

As part of the Saccharomyces Genome Deletion Project, sets of presumably isogenic haploid and diploid strains that differed only by single gene deletions were constructed. We found that one set of 96 strains (containing deletions of ORFs located between YOR097C and YOR192C) in the collection, which was derived from the haploid BY4741, has an additional mutation in the MSH3 mismatch repair gene.

Mosaicism for an FMR1 gene deletion in a fragile X female.

Most cases of fragile X syndrome result from expansion of CGG repeats in the FMR1 gene; deletions and point mutations of FMR1 are much less common. Mosaicism for an FMR1 full mutation with a deletion or with a normal allele has been reported in fragile X males. Here we report on a fragile X female who is mosaic for an FMR1 full mutation and an intragenic deletion.

Variation in efficiency of DNA mismatch repair at different sites in the yeast genome.

Evolutionary studies have suggested that mutation rates vary significantly at different positions in the eukaryotic genome. The mechanism that is responsible for this context-dependence of mutation rates is not understood. We demonstrate experimentally that frameshift mutation rates in yeast microsatellites depend on the genomic context and that this variation primarily reflects the context-dependence of the efficiency of DNA mismatch repair.

Microsatellite instability testing in colorectal carcinoma: choice of markers affects sensitivity of detection of mismatch repair-deficient tumors.

Purpose: Microsatellite instability (MSI) is found in 10% to 15% of sporadic colorectal tumors and is usually caused by defects in DNA mismatch repair (MMR). In 1997, a panel of microsatellite markers including mononucleotide and dinucleotide repeats was recommended by a National Cancer Institute workshop on MSI. We investigated the relationship between instability of these markers and MMR protein expression in a cohort of sporadic colorectal cancer patients.

Mutation rates in the complex microsatellite MYCL1 and related simple repeats in cultured human cells.

Microsatellite instability is a phenotype observed in tumors cells that have defects in DNA mismatch repair (MMR). Most markers used for detecting microsatellite instability are mono- and dinucleotide repeats, but one tetranucleotide repeat (MYCL1) has been reported to be useful for this purpose. The MYCL1 repeat is actually a complex repeat, made up of approximately 14 GAAA tetranucleotides plus various other GA-rich repeats.

Mutation frequency analysis of mononucleotide and dinucleotide repeats after oxidative stress.

Many tumors exhibit genetic instability at the DNA sequence level in the form of frameshift mutations in simple repeats (microsatellite instability). A high level of microsatellite instability, such as that seen in hereditary nonpolyposis colorectal cancer (HNPCC), arises from defects in the mismatch repair pathway. A low level of microsatellite instability is found in some non-HNPCC-associated cancers, such as those of the breast and lung, and is not attributable to mismatch repair defects.

Induction of a low level of microsatellite instability by overexpression of DNA polymerase Beta.

Microsatellite instability (MSI) is the condition in which high rates of frameshift mutations are observed in short tandem repeat sequences. Mutations in sequences of this type in coding regions of cancer-related genes can contribute to the development of cancer. Although defects in mismatch repair are usually responsible for high levels of MSI, low levels of MSI have been observed in some cancers with no known mismatch repair defects.

Sequence dependent instability of mononucleotide microsatellites in cultured mismatch repair proficient and deficient mammalian cells.

We have measured the mutation rates of G(17) and A(17) repeat sequences in cultured mammalian cells with and without mismatch repair and have compared these rates to those of a (CA)(17) repeat sequence. Plasmids containing microsatellites that disrupt the reading frame of a downstream neomycin-resistance gene were introduced into the cells by transfection and revertants were selected using the neomycin analog G418. Comparison of mutation rates within cell lines showed that the mutation rates of A(17) and (CA)(17) sequences were similar in the mismatch repair proficient cells, but the mutation rate of G(17) was significantly higher than that of either A(17) or (CA)(17).

Relative rates of insertion and deletion mutations in dinucleotide repeats of various lengths in mismatch repair proficient mouse and mismatch repair deficient human cells.

Microsatellites are DNA elements composed of short tandem repeats of 1-5bp. These sequences are particularly prone to frameshift mutation by insertion-deletion loop formation during replication. The mismatch repair system is responsible for correcting these replication errors, and microsatellite mutation rates are significantly elevated in the absence of mismatch repair.