Molecular origins of mutational spectra produced by the environmental carcinogen N -nitrosodimethylamine and S N 1 chemotherapeutic agents.

Autor:	Armijo AL; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Thongararm P; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Fedeles BI; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Yau J; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Kay JE; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Corrigan JJ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Chancharoen M; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Chawanthayatham S; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Samson LD; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Carrasco SE; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, NY 10065, USA., Engelward BP; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Fox JG; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Croy RG; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Essigmann JM; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2023 Mar 27; Vol. 5 (2), pp. zcad015. Date of Electronic Publication: 2023 Mar 27 (Print Publication: 2023).
DOI:	10.1093/narcan/zcad015
Abstrakt:	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 cancers treated with the DNA alkylator temozolomide (TMZ). When cells derived from the mice were treated with TMZ, N -methyl- N -nitrosourea, and streptozotocin (two other therapeutic methylating agents), all displayed NDMA-like HRMS, indicating mechanistically convergent mutational processes. The role of m6G in shaping the mutational spectrum of NDMA was probed by removing MGMT, the main cellular defense against m6G. MGMT-deficient mice displayed a strikingly enhanced mutant frequency, but identical HRMS, indicating that the mutational properties of these alkylators is likely owed to sequence-specific DNA binding. In sum, the HRMS of m6G-forming agents constitute an early-onset biomarker of exposure to DNA methylating carcinogens and drugs. (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
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