Characterization of the mechanism by which the rb/e2f pathway controls expression of the cancer genomic dna deaminase apobec3b

Pieter A. Roelofs, Chai Yeen Goh, Boon Haow Chua, Matthew C. Jarvis, Teneale A. Stewart, Jennifer L. McCann, Rebecca M. McDougle, Michael A. Carpenter, John W.M. Martens, Paul N. Span, Dennis Kappei, Reuben S. Harris

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

APOBEC3B (A3B)-catalyzed DNA cytosine deamination contributes to the overall mutational landscape in breast cancer. Molecular mechanisms responsible for A3B upregulation in cancer are poorly understood. Here, we show that a single E2F cis-element mediates repression in normal cells and that expression is activated by its mutational disruption in a reporter construct or the endogenous A3B gene. The same E2F site is required for A3B induction by polyomavirus T antigen indicating a shared molecular mechanism. Proteomic and biochemical experiments demonstrate binding of wildtype but not mutant E2F promoters by repressive PRC1.6/E2F6 and DREAM/E2F4 complexes. Knockdown and overexpression studies confirm involvement of these repressive complexes in regulating A3B expression. Altogether, these studies demonstrate that A3B expression is suppressed in normal cells by repressive E2F complexes and that viral or mutational disruption of this regulatory network triggers overexpression in breast cancer and provides fuel for tumor evolution.

Original languageEnglish (US)
Pages (from-to)1-64
Number of pages64
JournaleLife
Volume9
DOIs
StatePublished - Sep 2020
Externally publishedYes

Keywords

  • APOBEC3B
  • Cancer mutagenesis
  • Cell cycle regulation
  • DREAM complex
  • PRC1.6 complex
  • Polyomavirus T antigen
  • RB/E2F pathway
  • Transcriptional regulation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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