Hypermutable bases in the p53 cancer gene are at vulnerable positions in DNA secondary structures.
A DNA folding analysis indicates that the most hypermutable bases in exons 5, 7, and 8 of the p53 tumor suppressor gene are located immediately next to stems in stable DNA stem-loop structures. On the basis of the highest negative energy (-DeltaG) value of the structures containing each mutable bases and on the extent to which each base is unpaired during transcription, their relative mutabilities are calculated using a new computer algorithm. These predicted mutation frequencies correlate well with those observed in 14,000 human cancers (R(2) = 0.76), whereas there is no such correlation (R(2) = 0.0005) for nearby control bases. The correlation of hypermutable base frequencies with -DeltaG values is poor (R(2) = 0.19), indicating that the extent to which a base is unpaired during transcription is a significant contribution to predicting mutation frequencies.
Wright
Barbara E
BE
Division of Biological Sciences University of Montana, Missoula 59812, USA. bewright@selway.umt.edu
Reimers
Jacqueline M
JM
Schmidt
Karen H
KH
Reschke
Dennis K
DK
D001426:Bacterial Proteins; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D004269:DNA, Bacterial / Q000235:genetics / Q000502:physiology; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D004278:DNA, Superhelical / Q000737:chemistry / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics; D005091:Exons / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D056968:Lac Repressors; D009154:Mutation; D009690:Nucleic Acid Conformation; D012097:Repressor Proteins / Q000235:genetics; D013816:Thermodynamics
D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D029968:Escherichia coli Proteins; D056968:Lac Repressors; C539064:LacI protein, E coli; D012097:Repressor Proteins; D004247:DNA