Abstract
Mutation patterns of DNA adducts, such as mutational spectra and signatures, are useful tools for diagnostic and prognostic purposes. Mutational spectra of carcinogens derive from three sources: adduct formation, replication bypass, and repair. Here, we consider the repair aspect of 1,N6-ethenoadenine (εA) by the 2-oxoglutarate/Fe(II)-dependent AlkB family enzymes. Specifically, we investigated εA repair across 16 possible sequence contexts (5′/3′ flanking base to εA varied as G/A/T/C). The results revealed that repair efficiency is altered according to sequence, enzyme, and strand context (ss- versus ds-DNA). The methods can be used to study other aspects of mutational spectra or other pathways of repair.
Highlights
The human genome is constantly challenged by endogenous and exogenous sources, such as reactive oxygen species (ROS), ultraviolet (UV) light, and various carcinogens [1]
Researchers have developed two primary approaches to obtain these mutational features that capitalize on advances in large-scale sequencing technologies: a top-down approach referred to as mutational signatures and a bottom-up approach referred to as mutational spectra [5]
It is possible to obtain the mutational spectra of a certain carcinogen or adduct by assembling the mutational data that are individually generated from studies of one of the three aspects
Summary
The human genome is constantly challenged by endogenous and exogenous sources, such as reactive oxygen species (ROS), ultraviolet (UV) light, and various carcinogens [1] These DNA damaging agents form adducts and generate unique mutational patterns, which hold promise for cancer diagnosis and prevention [2,3,4]. There are several ways to obtain mutational spectra; one of them is to replicate a certain DNA adduct built in a site-specific modified genome in vitro or in living cells This bottom-up approach can be more laborious due to the consideration of multiple adducts and various cellular conditions; the results are not sensitive to false positives. It is possible to obtain the mutational spectra of a certain carcinogen or adduct by assembling the mutational data that are individually generated from studies of one of the three aspects. The methods reported here show the promise of using mutational spectra analyses to (1) investigate different aspects of the mutational processes of DNA lesions and (2) to construct mutational spectra of DNA damaging agents in a stepwise manner
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