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Mechanisms of APOBEC3 mutagenesis in human cancer cells

Author

Listed:
  • Mia Petljak

    (Broad Institute of MIT and Harvard)

  • Alexandra Dananberg

    (Memorial Sloan Kettering Cancer Center)

  • Kevan Chu

    (Memorial Sloan Kettering Cancer Center)

  • Erik N. Bergstrom

    (UC San Diego
    UC San Diego
    UC San Diego)

  • Josefine Striepen

    (Memorial Sloan Kettering Cancer Center)

  • Patrick Morgen

    (Memorial Sloan Kettering Cancer Center)

  • Yanyang Chen

    (Memorial Sloan Kettering Cancer Center)

  • Hina Shah

    (Memorial Sloan Kettering Cancer Center)

  • Julian E. Sale

    (Medical Research Council Laboratory of Molecular Biology
    Wellcome Sanger Institute)

  • Ludmil B. Alexandrov

    (UC San Diego
    UC San Diego
    UC San Diego)

  • Michael R. Stratton

    (Wellcome Sanger Institute)

  • John Maciejowski

    (Memorial Sloan Kettering Cancer Center)

Abstract

The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer1–3. However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time4. Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that APOBEC3A deletion diminished APOBEC3-associated mutational signatures. Deletion of both APOBEC3A and APOBEC3B further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of APOBEC3B increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures.

Suggested Citation

  • Mia Petljak & Alexandra Dananberg & Kevan Chu & Erik N. Bergstrom & Josefine Striepen & Patrick Morgen & Yanyang Chen & Hina Shah & Julian E. Sale & Ludmil B. Alexandrov & Michael R. Stratton & John M, 2022. "Mechanisms of APOBEC3 mutagenesis in human cancer cells," Nature, Nature, vol. 607(7920), pages 799-807, July.
  • Handle: RePEc:nat:nature:v:607:y:2022:i:7920:d:10.1038_s41586-022-04972-y
    DOI: 10.1038/s41586-022-04972-y
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    Cited by:

    1. 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.
    2. Hanjing Yang & Josue Pacheco & Kyumin Kim & Ayub Bokani & Fumiaki Ito & Diako Ebrahimi & Xiaojiang S. Chen, 2024. "Molecular mechanism for regulating APOBEC3G DNA editing function by the non-catalytic domain," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. 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.

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