Mismatch repair and cancer

Palombo, Fabio; Hughes, Melya J.; Jiricny, Josef; Truong, Oanh; Hsuan, J. Justin

doi:10.1038/367417a0

Cited by 71 publications

(23 citation statements)

References 16 publications

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“…Of 20 clones transfected with PMS2-WT, 5 were shown to express readily detectable levels of full-length PMS2 proteins (examples are given in VOL. 18,1998 hPMS2 MUTATION AND MUTATOR PHENOTYPES 1637 expected size (examples are given in Fig. 4B, lanes 4 to 6).…”

Section: Resultsmentioning

confidence: 99%

A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype

Nicolaides¹,

Littman

Modrich

et al. 1998

Molecular and Cellular Biology

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Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ line mutations in MMR genes predispose kindreds to HNPCC suggest a "two-hit" inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells containing a wild-type hPMS2 allele. These results have significant implications for understanding the relationship between mutagenesis and carcinogenesis and the ability to generate mammalian cells with mutator phenotypes.

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Section: Resultsmentioning

confidence: 99%

A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype

Nicolaides¹,

Littman

Modrich

et al. 1998

Molecular and Cellular Biology

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“…71 Up to date, very little is known about MSH2 expression in the brain. Using immunohistochemical analysis, we recently found that MSH2 is expressed in selective rat brain regions and it is induced by experimental paradigms of excitotoxicity.…”

Section: ± 63mentioning

confidence: 99%

Possible role of NF-κB and p53 in the glutamate-induced pro-apoptotic neuronal pathway

1999

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Apoptosis is now recognized as an important component in many progressive and acute neurodegenerative diseases. Extracellular signals and intracellular mechanisms triggering and regulating apoptosis in neuronal cells are still a matter of investigation. Here we review data from our and other laboratories with the aim to elucidate the nature of some proteins which are known to be involved in cell cycle regulation as well as in promoting degeneration and apoptosis of neurons. The following molecules will be taken into consideration: NF-kB, p53, p21 and MSH2. These proteins are activated by neurotoxic experimental conditions which involve the stimulation of selective receptors for the excitatory aminoacid glutamate. Thus, we hypothesize their contribution to an intracellular pathway responsible for the glutamateinduced neuronal death. Identification of such mechanisms could be relevant for understanding the apoptosis associated with various neurodegenerative diseases as well as for developing novel strategies of pharmacological intervention.

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“…Protease digestion studies suggested that the 100-kD polypeptide was a proteolytic fragment derived from the larger polypeptide (Hughes and Jiricny 1992!. However, subsequent amino acid sequencing analysis revealed that the 100-kD polypeptide corresponds to human Msh2; further analysis of the 160-kD polypeptide has not been reported (Palombo et al 1994). In yeast, an MSH2-dependent mismatch-binding activity was identified in nuclear extracts that displayed affinities for binding that correlated reasonably well to the efficiency of mismatch repair in vivo; however, these studies did not directly demonstrate that the observed protein-DNA complexes contained Msh2 {Miret et al 1993).…”

mentioning

confidence: 99%

The Saccharomyces cerevisiae Msh2 protein specifically binds to duplex oligonucleotides containing mismatched DNA base pairs and insertions.

Alani¹,

Chi²,

Kolodner³

1995

Genes Dev.

100

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The yeast Saccharomyces cerevisiae encodes four proteins, Mshl, Msh2, Msh3, Msh4, that show strong amino acid sequence similarity to MutS, a central component of the bacterial mutHLS mismatch repair system. MutS has been shown to recognize base pair mismatches in DNA in vitro. Previous studies have suggested that Msh2 is the major mismatch recognition protein in yeast. In this study, the 109-kD Msh2 polypeptide was overexpressed and purified to analyze its DNA-binding properties. This analysis demonstrated that Msh2 can bind selectively to duplex oligonucleotide substrates containing a G/T mismatch, 1-to 14-nucleotide insertion mismatches, and palindromic (12-to 14-nucleotide) insertion mismatches. A general trend was that the affinity of Msh2 for substrate was proportional to the size of the insertion mispair present (+ 14 PAL, + 12 PAL> + 14> + 8>GT, + 6, +4, +2, + 1}. Kinetic studies indicated that the specificity of Msh2 to mismatch substrates was a function of its ability to form stable complexes with mispair-containing duplex DNAs. These complexes decayed more slowly than Msh2 complexes formed with homoduplex DNA.

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Mismatch repair and cancer

Cited by 71 publications

References 16 publications

A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype

A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype

Possible role of NF-κB and p53 in the glutamate-induced pro-apoptotic neuronal pathway

The Saccharomyces cerevisiae Msh2 protein specifically binds to duplex oligonucleotides containing mismatched DNA base pairs and insertions.

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