DNA Deamination Is Required for Human APOBEC3A-Driven Hepatocellular Carcinoma In Vivo

Jordan A. Naumann, Prokopios P. Argyris, Michael A. Carpenter, Harshita B. Gupta, Yanjun Chen, Nuri A. Temiz, Yufan Zhou, Cameron Durfee, Joshua Proehl, Brenda L. Koniar, Silvestro G. Conticello, David A. Largaespada, William L. Brown, Hideki Aihara, Rachel I. Vogel, Reuben S. Harris

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Although the APOBEC3 family of single-stranded DNA cytosine deaminases is well-known for its antiviral factors, these enzymes are rapidly gaining attention as prominent sources of mutation in cancer. APOBEC3′s signature single-base substitutions, C-to-T and C-to-G in TCA and TCT motifs, are evident in over 70% of human malignancies and dominate the mutational landscape of numerous individual tumors. Recent murine studies have established cause-and-effect relationships, with both human APOBEC3A and APOBEC3B proving capable of promoting tumor formation in vivo. Here, we investigate the molecular mechanism of APOBEC3A-driven tumor development using the murine Fah liver complementation and regeneration system. First, we show that APOBEC3A alone is capable of driving tumor development (without Tp53 knockdown as utilized in prior studies). Second, we show that the catalytic glutamic acid residue of APOBEC3A (E72) is required for tumor formation. Third, we show that an APOBEC3A separation-of-function mutant with compromised DNA deamination activity and wildtype RNA-editing activity is defective in promoting tumor formation. Collectively, these results demonstrate that APOBEC3A is a “master driver” that fuels tumor formation through a DNA deamination-dependent mechanism.

Original languageEnglish (US)
Article number9305
JournalInternational journal of molecular sciences
Volume24
Issue number11
DOIs
StatePublished - Jun 2023

Keywords

  • APOBEC3A
  • carcinogenesis
  • DNA deamination
  • DNA mutation
  • hepatocellular carcinoma
  • molecular mechanism
  • RNA editing
  • tumorigenesis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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