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Hypermutable Bases in the p53 Cancer Gene Are at Vulnerable Positions in DNA Secondary Structures¹

Division of Biological Sciences University of Montana, Missoula, Montana 59812

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 (-G) 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 (R² = 0.76), whereas there is no such correlation (R² = 0.0005) for nearby control bases. The correlation of hypermutable base frequencies with -G values is poor (R² = 0.19), indicating that the extent to which a base is unpaired during transcription is a significant contribution to predicting mutation frequencies.

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