DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways

Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. We first summarize the current knowledge on the different sources and chemical nature of alkylating agents with a focus on relevant nitrosamines. Subsequently, we present the major DNA alkylation adducts induced by nitrosamines upon their metabolic activation by CYP450 monooxygenases. We then describe the DNA repair pathways engaged by the various DNA alkylation adducts, which include base excision repair, direct damage reversal by MGMT and ALKBH, as well as nucleotide excision repair. Their roles in the protection against the genotoxic and carcinogenic effects of nitrosamines are highlighted. Finally, we address DNA translesion synthesis as a DNA damage tolerance mechanism relevant to DNA alkylation adducts.

Automated summary

Nitrosamines, which are alkylating agents, are widely present in food, drinking water, cosmetics, and tobacco smoke, and can also be produced endogenously. Recently, nitrosamines have been found as impurities in various drugs, raising concerns due to their genotoxic and carcinogenic properties. In this article, we summarize the sources and chemical nature of alkylating agents, particularly relevant nitrosamines, and then discuss the DNA repair pathways involved in the protection against the genotoxic and carcinogenic effects of these compounds, including base excision repair, direct damage reversal by MGMT and ALKBH, nucleotide excision repair, and DNA translesion synthesis.