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

• Published in: Cell reports (Cambridge) 2021-03, Vol.34 (11), p.108864-108864, Article 108864
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: alkyladenine DNA glycosylase; Animals; Biomarkers, Tumor - metabolism; cancer; Cell Death; Chromosomal Instability - genetics; Diethylnitrosamine; Disease Susceptibility; DNA damage; DNA Damage - genetics; DNA Glycosylases - deficiency; DNA Glycosylases - metabolism; DNA Repair - genetics; DNA Replication - genetics; DNA strand break; Histones - metabolism; Homologous Recombination - genetics; liver; Liver - pathology; Liver Neoplasms - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Micronuclei, Chromosome-Defective; Mutagenesis - genetics; mutation; Neoplasms - genetics; Neoplasms - pathology; nitrosamine; Nitrosamines; Phenotype; Phosphoproteins - metabolism; Phosphorylation; replication-blocking lesion
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108864

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. [Display omitted] •AAG-initiated base excision repair modulates susceptibility to NDMA-induced disease•Low AAG increases susceptibility to methylation-induced mutations and liver cancer•High AAG activity sensitizes animals to hepatotoxicity and lethality from NDMA•Integration of phenotypes over time reveals progression of NDMA-induced pathologies The environmental contaminant N-nitrosodimethylamine (NDMA) creates replication-blocking 3-methyladenine (3MeA) DNA lesions. Here, Kay et al. demonstrate that excision of 3MeA by the AAG glycosylase to initiate base excision repair prevents NDMA-induced mutations and cancer in the mouse liver, but excess AAG activity leads to hepatotoxicity and animal lethality.