APOBEC3A catalyzes mutation and drives carcinogenesis in vivo

Emily K. Law; Rena Levin-Klein; Matthew C. Jarvis; Hyoung Kim; Prokopios P. Argyris; Michael A. Carpenter; Gabriel J. Starrett; Nuri A. Temiz; Lindsay K. Larson; Cameron Durfee; Michael B. Burns; Rachel I. Vogel; Spyridon Stavrou; Alexya N. Aguilera; Sandra Wagner; David A. Largaespada; Timothy K. Starr; Susan R. Ross; Reuben S. Harris

doi:10.1084/jem.20200261

APOBEC3A catalyzes mutation and drives carcinogenesis in vivo

Emily K. Law, Rena Levin-Klein, Matthew C. Jarvis, Hyoung Kim, Prokopios P. Argyris, Michael A. Carpenter, Gabriel J. Starrett, Nuri A. Temiz, Lindsay K. Larson, Cameron Durfee, Michael B. Burns, Rachel I. Vogel, Spyridon Stavrou, Alexya N. Aguilera, Sandra Wagner, David A. Largaespada, Timothy K. Starr, Susan R. Ross, Reuben S. Harris

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Abstract

The APOBEC3 family of antiviral DNA cytosine deaminases is implicated as the second largest source of mutation in cancer. This mutational process may be a causal driver or inconsequential passenger to the overall tumor phenotype. We show that human APOBEC3A expression in murine colon and liver tissues increases tumorigenesis. All other APOBEC3 family members, including APOBEC3B, fail to promote liver tumor formation. Tumor DNA sequences from APOBEC3A-expressing animals display hallmark APOBEC signature mutations in TCA/T motifs. Bioinformatic comparisons of the observed APOBEC3A mutation signature in murine tumors, previously reported APOBEC3A and APOBEC3B mutation signatures in yeast, and reanalyzed APOBEC mutation signatures in human tumor datasets support cause-and-effect relationships for APOBEC3A-catalyzed deamination and mutagenesis in driving multiple human cancers.

Original language	English (US)
Article number	e20200261
Journal	Journal of Experimental Medicine
Volume	217
Issue number	12
DOIs	https://doi.org/10.1084/jem.20200261
State	Published - Dec 7 2020

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© 2020 Law et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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Law, E. K., Levin-Klein, R., Jarvis, M. C., Kim, H., Argyris, P. P., Carpenter, M. A., Starrett, G. J., Temiz, N. A., Larson, L. K., Durfee, C., Burns, M. B., Vogel, R. I., Stavrou, S., Aguilera, A. N., Wagner, S., Largaespada, D. A., Starr, T. K., Ross, S. R., & Harris, R. S. (2020). APOBEC3A catalyzes mutation and drives carcinogenesis in vivo. Journal of Experimental Medicine, 217(12), Article e20200261. https://doi.org/10.1084/jem.20200261

Law, EK, Levin-Klein, R, Jarvis, MC, Kim, H, Argyris, PP, Carpenter, MA, Starrett, GJ, Temiz, NA, Larson, LK, Durfee, C, Burns, MB, Vogel, RI, Stavrou, S, Aguilera, AN, Wagner, S, Largaespada, DA, Starr, TK, Ross, SR & Harris, RS 2020, 'APOBEC3A catalyzes mutation and drives carcinogenesis in vivo', Journal of Experimental Medicine, vol. 217, no. 12, e20200261. https://doi.org/10.1084/jem.20200261

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APOBEC3A catalyzes mutation and drives carcinogenesis in vivo

Abstract

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