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Sequence-directed base mispairing in human oncogenes

L Lall¹, R L Davidson

¹Department of Molecular Genetics, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.

Molecular and Cellular Biology

|July 22, 1998

Summary

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Mutations in ras oncogenes often involve GC to AT transitions at codon 12. This study shows thymidine misincorporation preferentially targets the 3' G in GG doublets, explaining common ras oncogene activation in human tumors.

Area of Science:

Molecular Biology
Oncology
Genetics

Background:

Ras oncogenes are frequently mutated in human solid tumors, primarily through GC to AT transitions at codon 12.
Previous work indicated thymidine mutagenesis exhibits sequence specificity, favoring the 3' G of GG doublets.

Purpose of the Study:

To investigate the mechanism of sequence-directed thymidine mutagenesis.
To determine the relationship between thymidine misincorporation and ras oncogene activation in human tumors.

Main Methods:

In vitro DNA synthesis experiments using exonuclease-free Klenow polymerase in a repair-free environment.
Assessed the effect of local DNA sequence on base mispairing during DNA synthesis.

Main Results:

Related Experiment Videos

Deoxyribosylthymine (dT) misincorporation occurred significantly more efficiently opposite the 3' G than the 5' G of the GG doublet in codon 12.
The base upstream of the GG doublet influenced the differential dT misincorporation.
Within the GG doublet, the 5' G residue stimulated dT misincorporation opposite the 3' G, while the 3' G inhibited misincorporation opposite the 5' G.

Conclusions:

Sequence-directed dT misincorporation, particularly at the 3' G of codon 12 GG doublets, likely contributes to the common activation patterns of ras oncogenes in solid human tumors.