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An extended APOBEC3A mutation signature in cancer

Author

Listed:
  • Adam Langenbucher

    (Harvard Medical School)

  • Danae Bowen

    (University of California Irvine)

  • Ramin Sakhtemani

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School
    Wayne State University)

  • Elodie Bournique

    (University of California Irvine)

  • Jillian F. Wise

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School
    Broad Institute of Harvard and MIT
    University of Oslo)

  • Lee Zou

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School)

  • Ashok S. Bhagwat

    (Wayne State University
    Wayne State University School of Medicine)

  • Rémi Buisson

    (University of California Irvine
    University of California Irvine)

  • Michael S. Lawrence

    (Harvard Medical School
    Massachusetts General Hospital, Harvard Medical School
    Broad Institute of Harvard and MIT)

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.

Suggested Citation

  • Adam Langenbucher & Danae Bowen & Ramin Sakhtemani & Elodie Bournique & Jillian F. Wise & Lee Zou & Ashok S. Bhagwat & Rémi Buisson & Michael S. Lawrence, 2021. "An extended APOBEC3A mutation signature in cancer," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21891-0
    DOI: 10.1038/s41467-021-21891-0
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    Cited by:

    1. Yasha Butt & Ramin Sakhtemani & Rukshana Mohamad-Ramshan & Michael S. Lawrence & Ashok S. Bhagwat, 2024. "Distinguishing preferences of human APOBEC3A and APOBEC3B for cytosines in hairpin loops, and reflection of these preferences in APOBEC-signature cancer genome mutations," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Sujath Abbas & Oriol Pich & Ginny Devonshire & Shahriar A. Zamani & Annalise Katz-Summercorn & Sarah Killcoyne & Calvin Cheah & Barbara Nutzinger & Nicola Grehan & Nuria Lopez-Bigas & Rebecca C. Fitzg, 2023. "Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Ambrocio Sanchez & Pedro Ortega & Ramin Sakhtemani & Lavanya Manjunath & Sunwoo Oh & Elodie Bournique & Alexandrea Becker & Kyumin Kim & Cameron Durfee & Nuri Alpay Temiz & Xiaojiang S. Chen & Reuben , 2024. "Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Stefan Harjes & Harikrishnan M. Kurup & Amanda E. Rieffer & Maitsetseg Bayarjargal & Jana Filitcheva & Yongdong Su & Tracy K. Hale & Vyacheslav V. Filichev & Elena Harjes & Reuben S. Harris & Geoffrey, 2023. "Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Dillon S. McBride & Sofya K. Garushyants & John Franks & Andrew F. Magee & Steven H. Overend & Devra Huey & Amanda M. Williams & Seth A. Faith & Ahmed Kandeil & Sanja Trifkovic & Lance Miller & Trusha, 2023. "Accelerated evolution of SARS-CoV-2 in free-ranging white-tailed deer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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