Mechanisms of APOBEC3 mutagenesis in human cancer cells Journal Article

   


Authors: Petljak, M.; Dananberg, A.; Chu, K.; Bergstrom, E. N.; Striepen, J.; von Morgen, P.; Chen, Y.; Shah, H.; Sale, J. E.; Alexandrov, L. B.; Stratton, M. R.; Maciejowski, J.
Article Title: Mechanisms of APOBEC3 mutagenesis in human cancer cells
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. © 2022, The Author(s).
Keywords: genetics; neoplasm; neoplasms; proteins; metabolism; protein; pathology; cytidine deaminase; human genome; genome; mutagenesis; genome, human; clone; minor histocompatibility antigens; minor histocompatibility antigen; mutagenicity; cancer; humans; human; apolipoprotein b mrna editing enzyme catalytic polypeptide like; apobec3 protein, human; apobec3a protein, human; apobec3b protein, human; apobec deaminases
Journal Title: Nature
Volume: 607
Issue: 7920
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2022-07-28
Start Page: 799
End Page: 807
Language: English
DOI: 10.1038/s41586-022-04972-y
PUBMED: 35859169
PROVIDER: scopus
PMCID: PMC9329121
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85134529655&doi=10.1038%2fs41586-022-04972-y&partnerID=40&md5=01b4a78bd2b44a4da44aa085dbd4c6c3
Notes: Article -- Export Date: 2 September 2022 -- Source: Scopus
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MSK Authors
  1. John Maciejowski
    32 Maciejowski
  2. Yanyang Chen
    10 Chen
  3. Patrick Joel Von Morgen
    4 Von Morgen
  4. Alexandra Dananberg
    8 Dananberg
  5. Kevan Huai-Yee Chu
    5 Chu
  6. Josefine Ursel Striepen
    5 Striepen
  7. Hina Shah
    3 Shah
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