APOBEC3 cytidine deaminases in double-strand DNA break repair and cancer promotion

Abstract

High frequency of cytidine to thymidine conversions was identified in the genome of several types of cancer cells. In breast cancer cells, these mutations are clustered in long DNA regions associated with single-strand DNA (ssDNA), double-strand DNA breaks (DSB), and genomic rearrangements. The observed mutational pattern resembles the deamination signature of cytidine to uridine carried out by members of the APOBEC3 family of cellular deaminases. Consistently, APOBEC3B (A3B) was recently identified as the mutational source in breast cancer cells. A3G is another member of the cytidine deaminases family predominantly expressed in lymphoma cells, where it is involved in mutational DSB repair following ionizing radiation treatments. This activity provides us with a new paradigm for cancer cell survival and tumor promotion and a mechanistic link between ssDNA, DSBs, and clustered mutations. Cancer Res; 73(12); 3494-8. ©2013 AACR.

Figure 1

Deaminase-dependent and -independent models for A3G-mediated DSB repair. DSB end-resection by cellular nucleases/helicases (purple pacman) generates long ssDNA overhangs (blue ribbon). The ssDNA terminus is targeted by A3G multimers that mediate microhomology-based tethering in an interstrand synapse (IS) (1), facilitating MMEJ (2). A3G multimer disassembly generates multiple catalytic dimeric/monomeric mutational units (m), inducing C>U hypermutation of resected ssDNA (3). Uracil DNA glycosylase (UNG) catalyzes removal of the uracil from deoxyuridine, forming an abasic site (a) which is further cleaved by the base excision repair (BER) nuclease ApeI (4). Since A3G acts preferentially on the 3’ cytidine in a polycytidine tract, the truncated ssDNA is likely to end with two or more cytidines, reducing the search for microhomology by an incoming A3G multimer or other MMEJ factors (5). Terminal deamination by A3G may also promote DNA extension by the BER machinery. Alternatively, the MRN complex may associate with an abasic site and mediate cleavage of the ssDNA overhang (6). ssDNA end-bound MRN may then promote tethering of ssDNA termini, ATM activation (A) and recruitment of the NHEJ machinery (7).