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An extended APOBEC3A mutation signature in cancer
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An extended APOBEC3A mutation signature in cancer
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Journal Article
An extended APOBEC3A mutation signature in cancer
2021
Overview
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.
The APOBEC mutation signature contributes to a significant percentage of human cancers. Here the authors via biochemical and computational analyses shed light on how DNA primary sequence and secondary structure jointly influence A3A substrate optimality.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
