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PMID: 9488480 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype.

Molecular and cellular biology ·Vol. 18 ·No. 3 ·1998-03-00 ·Pages 1635-41

Nicolaides NC, Littman SJ, Modrich P, Kinzler KW, Vogelstein B

Abstract

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.

MeSH Terms
Adenosine Triphosphatases Animals Bacterial Proteins/metabolism Cell Line Cricetinae DNA Repair DNA Repair Enzymes DNA-Binding Proteins/metabolism Escherichia coli Proteins HeLa Cells Humans Mesocricetus Mismatch Repair Endonuclease PMS2 Multidrug Resistance-Associated Proteins MutL Proteins MutS Homolog 3 Protein Mutation Neoplasm Proteins/biosynthesis,genetics,metabolism Nucleic Acid Heteroduplexes Phenotype
Chemicals
Bacterial Proteins DNA-Binding Proteins Escherichia coli Proteins MSH3 protein, human Multidrug Resistance-Associated Proteins MutL protein, E coli MutS Homolog 3 Protein Neoplasm Proteins Nucleic Acid Heteroduplexes Adenosine Triphosphatases PMS2 protein, human Mismatch Repair Endonuclease PMS2 MutL Proteins DNA Repair Enzymes multidrug resistance-associated protein 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Nicolaides N C
Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA. [email protected]
Littman S J
Modrich P
Kinzler K W
Vogelstein B
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.18.3.1635
Email
[email protected]
Published
1998-03-00
Pages
1635-41
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC108878
Subset
IM
Grants
NCI NIH HHS · CA62924 · United States
NCI NIH HHS · CA71544 · United States
NCI NIH HHS · CA35494 · United States
External Links
PubMed source DOI: 10.1128/MCB.18.3.1635 PMC Full Text View journal details
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