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Mutagenesis Advance Access published online on March 8, 2005
Mutagenesis, doi:10.1093/mutage/gei014
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© The Authors 2005. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received December 22, 2004
Accepted February 2, 2005

Original article

Mutagenesis studies of the major benzo[a]pyrene N2-dG adduct in a 5'-TG versus a 5'-UG sequence: removal of the methyl group causes a modest decrease in the [G->T/G->A] mutational ratio

Arumugam Nagalingam 1, Kwang-Young Seo 1, and Edward L. Loechler 1*

1 Biology Department, Boston University, Boston, MA 02215, USA

* To whom correspondence should be addressed.
Edward L. Loechler, E-mail: loechler{at}bu.edu


  Abstract

The potent mutagen/carcinogen benzo[a]pyrene (B[a]P) is metabolically activated to (+)-anti-B[a]PDE, which induces a full spectrum of mutations primarily at the G:C base pairs (e.g. GC->TA, GC->AT, etc.). Each of these mutations can be induced by its major adduct [+ta]-B[a]P-N2-dG, where DNA sequence context appears to influence both the quantitative and qualitative pattern of mutagenesis. We noted previously that 5'-TG sequences tend to have a higher fraction of G->T mutations for both [+ta]-B[a]P-N2-dG and (+)-anti-B[a]PDE in comparison with 5'-CG, 5'-GG or 5'-AG sequences. To investigate a possible structural element for this trend, the role (if any) of the methyl group on the 5'-T is considered. Using adduct site-specific means, the [G->T/G->A] mutational ratio for [+ta]-B[a]P-N2-dG is determined to be ~1.08 in a 5'-TGT sequence, and ~0.60 in a 5'-UGT sequence. (G->C mutations are minor.) Although this modest ~1.8-fold decrease in [G->T/G->A] ratio is statistically significant (P = 0.03), it suggests that the methyl group on the 5'-T is not the main reason why a 5'-T tends to enhance G->T mutations. This study was prompted by an adduct conformational hypothesis, which predicted that the removal of the methyl group in a 5'-TG sequence would lower the fraction of G->T mutations; however, the ~1.8-fold decrease is too small to do additional experiments to assess whether this conformational hypothesis, or other hypotheses, are the true cause of the decrease, which is discussed in this paper.


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