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An extended APOBEC3A mutation signature in cancer
Adam Langenbucher1, Danae Bowen2, Ramin Sakhtemani1,3,4
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
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.
Insights
DNA structure, not just sequence, influences APOBEC3A (A3A) mutagenesis in cancer. Optimal DNA hairpins can make non-TpC sites hotspots, explaining the genomic Twin Paradox.
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- APOBEC mutagenesis is a key driver of cancer evolution, primarily targeting TpC sites.
- Previous work identified DNA hairpin loops as a target for APOBEC3A (A3A).
Purpose of the Study:
- To investigate the role of DNA secondary structure in APOBEC3A (A3A) substrate selection.
- To elucidate the mechanism behind the genomic Twin Paradox in cancer genomes.
Main Methods:
- Analysis of APOBEC3A (A3A) activity on DNA substrates with varying sequences and secondary structures.
- Genomic data analysis to identify mutation patterns and correlate them with DNA structure.
Main Results:
- DNA secondary structure significantly influences A3A substrate preference, sometimes overriding the canonical TpC sequence preference.
- Non-TpC sites within optimal DNA hairpins can function as potent mutational hotspots.
- The genomic Twin Paradox, characterized by adjacent TpC and VpC mutation hotspots, is explained by both sites being optimal A3A substrates due to favorable DNA structures.
Conclusions:
- DNA secondary structure plays an orthogonal role to DNA sequence in determining APOBEC mutagenesis patterns.
- The concept of a mutation signature needs to incorporate both sequence and structural DNA features.
- This research provides a new framework for understanding cancer evolution driven by APOBEC enzymes.
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