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

Jennifer E Kay; Joshua J Corrigan; Amanda L Armijo; Ilana S Nazari; Ishwar N Kohale; Dorothea K Torous; Svetlana L Avlasevich; Robert G Croy; Dushan N Wadduwage; Sebastian E Carrasco; Stephen D Dertinger; Forest M White; John M Essigmann; Leona D Samson; Bevin P Engelward

doi:10.1016/j.celrep.2021.108864

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

Cell Rep. 2021 Mar 16;34(11):108864. doi: 10.1016/j.celrep.2021.108864.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 01239, USA.
⁴ 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.
⁵ Litron Laboratories, Rochester, NY 14623, USA.
⁶ The John Harvard Distinguished Science Fellows Program, Harvard University, Cambridge, MA 02138, USA; Center for Advanced Imaging, Harvard University, Cambridge, MA 02138, USA.
⁷ Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 01239, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.

Abstract

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.

Keywords: DNA damage; DNA strand break; alkyladenine DNA glycosylase; cancer; liver; mutation; nitrosamine; replication-blocking lesion.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers, Tumor / metabolism
Cell Death
Chromosomal Instability / genetics
DNA Damage / genetics
DNA Glycosylases / deficiency
DNA Glycosylases / metabolism
DNA Repair / genetics
DNA Replication / genetics*
Diethylnitrosamine
Disease Susceptibility
Histones / metabolism
Homologous Recombination / genetics
Liver / pathology
Liver Neoplasms / pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Micronuclei, Chromosome-Defective
Mutagenesis / genetics*
Neoplasms / genetics*
Neoplasms / pathology*
Nitrosamines
Phenotype
Phosphoproteins / metabolism
Phosphorylation

Substances

Biomarkers, Tumor
H2AX protein, mouse
Histones
Nitrosamines
Phosphoproteins
Diethylnitrosamine
3-methyladenine-DNA glycosylase
DNA Glycosylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding