Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair

Strand, Micheline K.; Ta, Prolla; Rm, Liskay; Td, Petes

doi:10.1038/365274a0

Cited by 980 publications

(672 citation statements)

References 20 publications

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“…The elevated mutation frequency in MSH2 7/7 mice (4.8 ± 15.2-fold) is consistent with the increase in mutation frequency observed in mutS Escherichia coli (Dohet et al, 1985;Schaaper and Dunn, 1987) and MSH2 de®cient Saccharomyces cerevisiae (Reenan and Kolodner, 1992;Strand et al, 1993). High hprt gene mutation frequencies were also observed in murine MSH2 de®cient embryonic stem cells (de Wind et al, 1995), and in human tumor cell lines with MMR de®ciencies (Kat et al, 1993;Bhattacharyya et al, 1994;Eshleman et al, 1995;Branch et al, 1995).…”

Section: Discussionsupporting

confidence: 78%

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice

et al. 1997

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Tumors derived from individuals with hereditary nonpolyposis colorectal cancer syndrome frequently demonstrate mutations in both alleles of hMSH2, a key gene in DNA mismatch repair (MMR). Sporadic tumors also frequently exhibit MMR de®ciency. In keeping with the role of MMR in the maintenance of genome integrity, mice de®cient in MSH2 via gene targeting demonstrate a high incidence of thymic lymphomas and small intestinal adenocarcinomas. To investigate the e ects of MSH2 de®ciency in normal tissues, mice containing a retrievable transgenic lacI reporter gene for mutation detection were crossed with MSH2 7/7 mice. Mice homozygous for MSH2 de®ciency revealed 4.8, 11.0 and 15.2-fold elevations in spontaneous mutation frequency in DNA obtained from brain, small intestine, and thymus, respectively, as compared to heterozygous or wild-type mice. Mutations most frequently recovered from MSH2 7/7 mice were single base substitutions (77%), particularly base transitions (64%). Frameshifts occurred less frequently (19%) and fell within very short (3 ± 5 bp) mononucleotide runs. Thus the number of key growth control genes potentially impacted by MMR de®ciency extends beyond those containing repetitive sequences. These results highlight the capacity for MSH2 de®ciency to serve as a potent driving force during the multi-step evolution of tumors.

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Section: Discussionsupporting

confidence: 78%

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice

et al. 1997

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“…Petes and colleagues tested the stability of poly(dGT) tracts in S. cerevisiae cells harbouring single and double mutations in MMR genes MSH2, MLH1, and PMS1 (Strand et al, 1993). Loss of any one MMR gene was sufficient to elevate the frequency of tract instability two orders of magnitude.…”

Section: Mmr Defects and Human Cancermentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

376

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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“…For short microsatellites, both mechanisms have been reported. However, in longer microsatellite tracts, MMR becomes the favored mechanism [12,17] because proofreading ability decreases as the length of the repeat increases [12,[17][18][19]. Although polymerase utilization of slipped DNA intermediates is a requisite step in this model, the cellular polymerase(s) responsible for microsatellite mutagenesis are not known.…”

Section: Introductionmentioning

confidence: 99%

Escherichia coli DNA polymerase IV contributes to spontaneous mutagenesis at coding sequences but not microsatellite alleles

Jacob

Eckert

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Slipped strand mispairing during DNA synthesis is one proposed mechanism for microsatellite or short tandem repeat (STR) mutation. However, the DNA polymerase(s) responsible for STR mutagenesis have not been determined. In this study, we investigated the effect of the Escherichia coli dinB gene product (Pol IV) on mononucleotide and dinucleotide repeat stability, using an HSVtk gene episomal reporter system for microsatellite mutations. For the control vector (HSV-tk gene only) we observed a statistically significant 3.5-fold lower median mutation frequency in dinB -than dinB + cells (p<0.001, Wilcoxon Mann Whitney Test). For vectors containing an in-frame mononucleotide allele ([G/C] 10 ) or either of two dinucleotide alleles ([GT/CA] 10 and [TC/AG] 11 ) we observed no statistically significant difference in the overall HSV-tk mutation frequency observed between dinB + and dinB -strains. To determine if a mutational bias exists for mutations made by Pol IV, mutational spectra were generated for each STR vector and strain. No statistically significant differences between strains were observed for either the proportion of mutational events at the STR or STR specificity among the three vectors. However, the specificity of mutational events at the STR alleles in each strain varied in a statistically significant manner as a consequence of microsatellite sequence. Our results indicate that while Pol IV contributes to spontaneous mutations within the HSV-tk coding sequence, Pol IV does not play a significant role in spontaneous mutagenesis at [G/ C] 10 , [GT/CA] 10 , or [TC/AG] 11 microsatellite alleles. Our data demonstrate that in a wild type genetic background, the major factor influencing microsatellite mutagenesis is the allelic sequence composition.

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Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair

Cited by 980 publications

References 20 publications

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Escherichia coli DNA polymerase IV contributes to spontaneous mutagenesis at coding sequences but not microsatellite alleles

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