Carcinogenesis, Vol 18, 1311-1318, Copyright © 1997 by Oxford University Press
L Arcangeli, J Simonetti, C Pongratz and KJ Williams
Defective mismatch repair has recently been implicated as the major
contributor towards the mutator phenotype observed in tumour cell lines
derived from patients diagnosed with hereditary non-polyposis colon cancer
(HNPCC). Cell lines from other cancer-prone syndromes, such as xeroderma
pigmentosum, have been found to be defective in nucleotide excision repair
of damaged bases. Some genetic complementation groups are defective
specifically in transcription-coupled excision repair, although this type
of repair defect has not been associated with cancer proneness. Mechanisms
contributing to the high incidence of activating point mutations in
oncogenes (such as H-ras codon 12) are not understood. It is possible that
novel mechanisms of misrepair or misreplication occur at these sites in
addition to the above DNA repair mechanisms. In this study, we have
compared the rate of strand-directed mismatch repair of four mispairs (G:A,
A:C, T:C and G:T) at the H-ras codon 12, middle G:C position. Our results
indicate that, although this location is not a 'hot spot' for bacterial
mismatch repair, it is a 'hot spot' for decreased repair of specific
mismatched bases within NIH 3T3 cells. NIH 3T3, unlike Escherichia coli,
have an extremely low repair rate of the G:A mispair (35%), as well as the
A:C mispair (58%) at this location. NIH 3T3 also have a moderately low
repair rate of the T:C mispair (80%) at the codon 12 location. Conversely,
NIH 3T3 repair of G:T (100%) is comparable to E. coli repair (94%) of this
mismatch. These results demonstrate that a mismatch containing an incorrect
adenine on either strand at the H-ras codon 12 middle base pair location is
most likely to undergo a mutational event in NIH 3T3 cells. Conversely, a
mismatch containing an incorrect thymine in the transcribed strand is least
likely to undergo a mutational event.
ARTICLES
Site- and strand-specific mismatch repair of human H-ras genomic DNA in a mammalian cell line
Biomedical Program and Department of Biological Sciences, University of Alaska, Anchorage 99508, USA.
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