Carcinogen-induced DNA structural distortion differences in the <i>RAS</i> gene isoforms; the importance of local sequence



Menzies, Georgina E, Prior, Ian A ORCID: 0000-0002-4055-5161, Brancale, Andrea, Reed, Simon H and Lewis, Paul D
(2021) Carcinogen-induced DNA structural distortion differences in the <i>RAS</i> gene isoforms; the importance of local sequence. BMC CHEMISTRY, 15 (1). 51-.

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Abstract

<h4>Background</h4>Local sequence context is known to have an impact on the mutational pattern seen in cancer. The RAS genes and a smoking carcinogen, Benzo[a]pyrene diol epoxide (BPDE), have been utilised to explore these context effects. BPDE is known to form an adduct at the guanines in a number of RAS gene sites, KRAS codons 12, 13 and 14, NRAS codon 12, and HRAS codons 12 and 14.<h4>Results</h4>Molecular modelling techniques, along with multivariate analysis, have been utilised to determine the sequence influenced differences between BPDE-adducted RAS gene sequences as well as the local distortion caused by the adducts.<h4>Conclusions</h4>We conclude that G:C > T:A mutations at KRAS codon 12 in the tumours of lung cancer patients (who smoke), proposed to be predominantly caused by BPDE, are due to the effect of the interaction methyl group at the C5 position of the thymine base in the KRAS sequence with the BPDE carcinogen investigated causing increased distortion. We further suggest methylated cytosine would have a similar effect, showing the importance of methylation in cancer development.

Item Type: Article
Uncontrolled Keywords: Sequence context, Mutation rates, RAS genes, Molecular dynamics, DNA, Structural distortion, Benzo[a]pyrene diol epoxide
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 28 Sep 2021 10:29
Last Modified: 18 Oct 2023 08:44
DOI: 10.1186/s13065-021-00777-8
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3138572