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 tumors.
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.
Schmutte
C
C
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California, School of Medicine, Los Angeles 90033-0800, USA.
Yang
A S
AS
Beart
R W
RW
Jones
P A
PA
D001483:Base Sequence; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D045647:DNA Glycosylases; D004260:DNA Repair; D043224:Deoxyribonuclease (Pyrimidine Dimer); D004706:Endodeoxyribonucleases / Q000378:metabolism*; D016158:Genes, p53 / Q000235:genetics*; D006147:Guanine / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics*; D013941:Thymine / Q000378:metabolism*; D014498:Uracil / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase
D014498:Uracil; D006147:Guanine; D004706:Endodeoxyribonucleases; D043224:Deoxyribonuclease (Pyrimidine Dimer); D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase; D013941:Thymine