Year: 2021
Type: article
Abstract: APOBEC mutagenesis, a major driver of cancer evolution, is known for targeting TpC sites in DNA. Recently, we showed that APOBEC3A (A3A) targets DNA hairpin loops. Here, we show that DNA secondary structure is in fact an orthogonal influence on A3A substrate optimality and, surprisingly, can override the TpC sequence preference. VpC (non-TpC) sites in optimal hairpins can outperform TpC sites as mutational hotspots. This expanded understanding of APOBEC mutagenesis illuminates the genomic Twin Paradox, a puzzling pattern of closely spaced mutation hotspots in cancer genomes, in which one is a canonical TpC site but the other is a VpC site, and double mutants are seen only in trans, suggesting a two-hit driver event. Our results clarify this paradox, revealing that both hotspots in these twins are optimal A3A substrates. Our findings reshape the notion of a mutation signature, highlighting the additive roles played by DNA sequence and DNA structure.
Source: Nature Communications
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,560
Funders: U.S. Department of Health and Human Services, Concern Foundation, California Breast Cancer Research Program, Cancer Research Coordinating Committee, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Chao Family Comprehensive Cancer Center
Awards: Mechanisms driving lung cancer evolution during targeted kinase inhibitor treatment, G1315042094, G1991233780, G3735276934, G4205495278, Targeting APOBEC3A-expressing cancer cells with ATR inhibitors, G4677119456, Impacts of APOBECs on DNA replication, ATR checkpoint, and cancer therapy, G5582200092, G6003535633, G6060788450, G618150926, G7285880520, TARGETING APOBEC3A-EXPRESSING CANCER CELLS WITH ATR INHIBITORS, Mapping and Visualizing Uracils Created by AID/APOBEC Enzymes using UdgX, G9000019938, Cancer Center Support Grant
OpenAlex ID: W3133827704