An extended APOBEC3A mutation signature in cancer

Adam Langenbucher,Ramin Sakhtemani,Rémi Buisson,Michael S Lawrence,Danae Bowen,Ashok S Bhagwat,Elodie Bournique,Jillian F Wise,Lee Zou

doi:10.1038/s41467-021-21891-0

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.

Highlights

APOBEC mutagenesis, a major driver of cancer evolution, is known for targeting TpC sites in DNA
Recognizing the important effect of DNA secondary structure on A3A substrate optimality, here we set out to revisit the traditional definition of the APOBEC mutation signature, this time agnostic of primary sequence, and without assuming that A3A acts on unstructured substrates
APOBEC3A is capable of deaminating VpC sites in DNA hairpins in vitro

Summary

Introduction

APOBEC mutagenesis, a major driver of cancer evolution, is known for targeting TpC sites in DNA. 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. We are able to resolve the genomic Twin Paradox, by revealing that both sites in the twin hotspots are structurally optimal A3A substrates, suggesting that these twin mutation hotspots are likely twin passenger events due to A3A activity

Methods

Results

Conclusion