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.

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