DNA repair pathways maintain the integrity of the genome, prevent the onset of mutations and genetic change that leads to cancer, disease and aging phenotypes and play a significant role in the cellular and organismal response to environmental exposures. As such, identifying a defect in DNA repair capacity or in the cellular response to endogenous or environmental stresses is a precision prevention strategy that may help identify those at high risk from environmental genotoxins. However, functional defects require a direct analysis of basal genome integrity and a direct measure of the cellular capacity to repair the genome in response to exogenous genotoxins. To clarify DNA repair pathway-specific DNA damage and repair fingerprints, we have begun a program to iteratively define (i) the cellular response induced by a spectrum of DNA damaging agents, (ii) the impact on the cellular response by DNA damage response modifiers and (iii) the change in signature in human cells with defined deletions (knockouts) in genes across all DNA repair pathways. The DNA Repair Pathway (DRP) signature or fingerprint includes classical genotoxic analyses including cell survival, apoptosis and cell cycle effects. Further, both basal and induced DNA damage levels as well as genomic DNA repair kinetics are quantified using a 96-well CometChip platform. In this initial cohort analysis, we describe the DRP-fingerprint of base excision repair (BER) deficiency, employing cells with gene deletions in base damage repair (OGG1) as well as key components of BER including XRCC1, Polβ and PARP1. Finally, we will present an analysis of 40 environmental compounds to begin to define those genotoxins that trigger BER-specific DNA damage. Our overall goal is to further classify genotoxins based on DNA repair pathway involvement using our DRP-fingerprint analysis platform.

Developing DNA repair pathway specific genotoxic signatures

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.