Molecular origins of mutational spectra produced by the environmental carcinogen N-nitrosodimethylamine and S_N1 chemotherapeutic agents.

ABSTRACT: DNA-methylating environmental carcinogens such as N-nitrosodimethylamine (NDMA) and certain alkylators used in chemotherapy form O ⁶-methylguanine (m6G) as a functionally critical intermediate. NDMA is a multi-organ carcinogen found in contaminated water, polluted air, preserved foods, tobacco products, and many pharmaceuticals. Only ten weeks after exposure to NDMA, neonatally-treated mice experienced elevated mutation frequencies in liver, lung and kidney of ∼35-fold, 4-fold and 2-fold, respectively. High-resolution mutational spectra (HRMS) of liver and lung revealed distinctive patterns dominated by GC→AT mutations in 5'-Pu-G-3' contexts, very similar to human COSMIC mutational signature SBS11. Commonly associated with alkylation damage, SBS11 appears in cancer

SUBMITTER: Armijo AL 

PROVIDER: S-EPMC10041537 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature