Mechanisms of APOBEC3 mutagenesis in human cancer cells

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 () and John Maciejowski ()
Additional contact information
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
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
Ludmil B. Alexandrov: UC San Diego
Michael R. Stratton: Wellcome Sanger Institute
John Maciejowski: Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 607, issue 7920, 799-807

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04972-y

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