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

Autor: Ishwar N. Kohale, Joshua J. Corrigan, Ilana S. Nazari, Leona D. Samson, Forest M. White, Sebastian E. Carrasco, Robert G. Croy, Dushan N. Wadduwage, Amanda L. Armijo, Jennifer E. Kay, Bevin P. Engelward, Stephen D. Dertinger, John M. Essigmann, Svetlana L. Avlasevich, Dorothea K. Torous
Rok vydání: 2021
Předmět:
0301 basic medicine
DNA Replication
Nitrosamines
DNA Repair
DNA damage
Mice
Transgenic
medicine.disease_cause
General Biochemistry
Genetics and Molecular Biology
DNA Strand Break
Article
DNA Glycosylases
Histones
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Chromosomal Instability
Neoplasms
DNA Repair Protein
polycyclic compounds
Biomarkers
Tumor
medicine
Animals
Diethylnitrosamine
Phosphorylation
Homologous Recombination
Cytotoxicity
Micronuclei
Chromosome-Defective
Mutation
Cell Death
Liver Neoplasms
Cancer
Base excision repair
Phosphoproteins
medicine.disease
Mice
Inbred C57BL
030104 developmental biology
Phenotype
Liver
chemistry
Mutagenesis
Nitrosamine
DNA glycosylase
Cancer research
Lethality
Disease Susceptibility
030217 neurology & neurosurgery
DNA Damage
Zdroj: Cell Rep
Elsevier
DOI: 10.1101/2021.01.12.426356
Popis: SummaryN-nitrosodimethylamine (NDMA) is a DNA methylating agent that has been discovered to contaminate water, food and drugs. The alkyladenine glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we studied Aag−/− and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine, or 3MeA) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switched from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrated a suite of molecular, cellular and physiological analyses. We found 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 tips the balance between blocks and breaks, and thus dictates the disease consequences of DNA damage.
Databáze: OpenAIRE
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