Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice.

Autor:	Kay JE; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Corrigan JJ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Armijo AL; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Nazari IS; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Kohale IN; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Torous DK; Litron Laboratories, Rochester, NY 14623, USA., Avlasevich SL; Litron Laboratories, Rochester, NY 14623, USA., Croy RG; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Wadduwage DN; The John Harvard Distinguished Science Fellows Program, Harvard University, Cambridge, MA 02138, USA; Center for Advanced Imaging, Harvard University, Cambridge, MA 02138, USA., Carrasco SE; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Dertinger SD; Litron Laboratories, Rochester, NY 14623, USA., White FM; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Essigmann JM; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Samson LD; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 01239, USA., Engelward BP; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA; Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 01239, USA. Electronic address: bevin@mit.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Mar 16; Vol. 34 (11), pp. 108864.
DOI:	10.1016/j.celrep.2021.108864
Abstrakt:	N-Nitrosodimethylamine (NDMA) is a DNA-methylating agent that has been discovered to contaminate water, food, and drugs. The alkyladenine DNA glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we study Aag-knockout (Aag -/- ) and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine [3MeA]) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switches from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrate a suite of molecular, cellular, and physiological analyses. We find that unrepaired 3MeA is somewhat toxic, but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tip the balance between blocks and breaks and thus dictate the disease consequences of DNA damage. Competing Interests: Declaration of interests S.L.A., D.K.T., and S.D.D. are employees of Litron Laboratories. Litron plans to sell kits for scoring micronucleated mouse hepatocytes via flow cytometry as described herein (In Vivo MicroFlow PLUS ML kits). (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu