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Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice.
Kay, Jennifer E; Corrigan, Joshua J; Armijo, Amanda L; Nazari, Ilana S; Kohale, Ishwar N; Torous, Dorothea K; Avlasevich, Svetlana L; Croy, Robert G; Wadduwage, Dushan N; Carrasco, Sebastian E; Dertinger, Stephen D; White, Forest M; Essigmann, John M; Samson, Leona D; Engelward, Bevin P.
Afiliação
  • 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 012
  • 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 Techno
  • 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 Techno
  • 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.
Cell Rep ; 34(11): 108864, 2021 03 16.
Article em En | MEDLINE | ID: mdl-33730582
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Mutagênese / Replicação do DNA / Neoplasias Limite: Animals Idioma: En Revista: Cell Rep Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Mutagênese / Replicação do DNA / Neoplasias Limite: Animals Idioma: En Revista: Cell Rep Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos