Novel Substrates for DNA Cytidine Deaminase APOBEC3B with Possible Implications for Alkylating Agent Chemotherapy

Abstract

Mutations mediated by APOBEC3B (A3B), a single‐strand specific cytidine deaminase, are common in various human cancers, often occurring in long, strand‐coordinated clusters, but also as isolated lesions. The clusters are thought to result from transient single‐stranded DNA generated during replication, recombination, transcription, or, as we recently adduced, DNA repair. A3B has a strong preference for C in a 5′‐TpC‐3′ (TpC) context and catalyzes hydrolysis of the primary amine to generate uracil. Subsequent repair results in mutation of C's to approximately equal numbers of transitions (T) and transversions (A or G), by which A3B‐mediated mutations are identified. We report here that A3B, in some instances, can deaminate cytosine residues in a double‐stranded DNA context in vitro. For example, a C paired to O6‐methylguanine (O6meG), if in a TpC context, is deaminated by A3B, likely due to weak hydrogen bonding between the cytosine primary amine and the guanine carbonyl group. Additionally, an abasic (AP) site opposite a C, or adjacent to the G of a C/G pair, renders the C susceptible to deamination. These results could account for the isolated, non‐clustered A3B mutations observed in many cancers. However, AP sites are common DNA lesions, and O6meG levels increase under alkylating conditions caused by environmental nitrosamines and certain chemotherapeutic treatments. Therefore, these foci could contribute to A3B‐mediated mutations in all cells.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.