Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Publication date: Available online 2 December 2015 Source:Mutation Research/Reviews in Mutation Research Author(s): Joanna Klapacz, Lynn H. Pottenger, Bevin P. Engelward, Christopher D. Heinen, George E. Johnson, Rebecca A. Clewell, Paul L. Carmichael, Yeyejide Adeleye, Melvin E. Andersen From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mut...
Source: Mutation Research Reviews in Mutation Research - Category: Genetics & Stem Cells Source Type: research