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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Sep 13;91(19):8905–8909. doi: 10.1073/pnas.91.19.8905

A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype.

G Aquilina 1, P Hess 1, P Branch 1, C MacGeoch 1, I Casciano 1, P Karran 1, M Bignami 1
PMCID: PMC44715  PMID: 8090742

Abstract

We have analyzed spontaneous mutations in the adenine phosphoribosyltransferase gene of Chinese hamster clone B cells that exhibit a mutator phenotype because of defective mismatch binding. The mutator phenotype conferred increases in a limited number of mutational classes. The rates of transitions and most transversions were not significantly increased. The rates of A to T transversions and -2 frameshifts were strikingly elevated. These mutations were in repeated elements and 5 of 9 of the frameshifts were dinucleotide deletions in DNA sequences resembling microsatellites. The mismatch binding protein that is defective in the mutator line is a G-T mismatch recognition factor. Band-shift analysis indicated that the preferred substrate for the mismatch recognition protein is duplex DNA containing an extrahelical mono- or dinucleotide within repeated sequences. In agreement with a role in preventing minus frameshifts, a defective binding protein conferred an instability in clone B microsatellite DNA. A mismatch binding defect was also detected in Lo Vo, a human colorectal carcinoma cell line. Extracts of clone B or a second mismatch binding-deficient line, Raji-F12, did not complement Lo Vo extracts, indicating that these lines share a common defect. Our data provide a mechanistic explanation for the relation between defective mismatch recognition and the microsatellite instability of human colon cancer.

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