An extended APOBEC3A mutation signature in cancer

Adam Langenbucher, Danae Bowen, Ramin Sakhtemani, Elodie Bournique, Jillian F. Wise, Lee Zou (), Ashok S. Bhagwat (), Rémi Buisson () and Michael S. Lawrence ()
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Adam Langenbucher: Harvard Medical School
Danae Bowen: University of California Irvine
Ramin Sakhtemani: Harvard Medical School
Elodie Bournique: University of California Irvine
Jillian F. Wise: Harvard Medical School
Lee Zou: Harvard Medical School
Ashok S. Bhagwat: Wayne State University
Rémi Buisson: University of California Irvine
Michael S. Lawrence: Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21891-0

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