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Base Excision Repair of U:G Mismatches at a Mutational Hotspot in the p53 Gene Is More Efficient Than Base Excision Repair of T:G Mismatches in Extracts of Human Colon Tumors¹

Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California, School of Medicine, Los Angeles, California 90033-0800

Approximately 50% of mutations that inactivate the p53 tumor suppressor gene in the germline and in colon tumors are C to T transitions at methylation sites (CpG sites). These mutations are believed to be caused by an endogenous mechanism and spontaneous deamination of 5-methyl-cytosine to T is likely to contribute significantly to this high mutation rate. The resulting T:G mismatches created by this process have been hypothesized to be less efficiently repaired than U:G mismatches formed by deamination of C. We have, therefore, performed the first study to directly compare rates of T:G versus U:G base excision repair at identical sites observed to be mutated in the p53 gene using extracts of human normal colon mucosa and colon carcinoma tissue. Mismatched U was excised up to 6000-fold more efficiently than T, suggesting that differences in repair efficiencies are the major source of C to T transition mutations at CpG sites in human tissues. The data also suggests that T:G mismatches are repaired by additional mechanisms in human cells.

¹ This work is supported by Grant R35 CA49758 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Kenneth Norris Jr. Comprehensive Cancer Center, University of Southern California, P. O. Box 33800, 1441 Eastlake Avenue, Los Angeles, CA 90033-0800.

Received 6/ 5/95. Accepted 7/24/95.

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