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

12 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

Bibliographical note

Funding Information:
to derepress A3B and gain an evolutionary advantage. This possibility is also supported by

Funding Information:
These studies were supported in part by the Minnesota Ovarian Cancer Alliance (to RSH), P01 CA234228 (to RSH), KWF10270 (to JM, PS, and RSH), and University of Minnesota College of Biological Sciences and Academic Health Center (to RSH). Research in the Kappei laboratory was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative and an NMRC Open Fund Young Individual Research Grant (NMRC/OFYIRG/055/2017). Salary support for MCJ was provided in part by T32-CA009138 and subsequently F31-CA243306. Salary support for TAS was provided in part by a Fellowship from the Susan G. Komen Foundation. Salary support for BHC was provided in part by a postgraduate fellowship awarded by the Cancer Science Institute (CSI) of Singapore and an NUSMed Postdoctoral Fellowship (NUSMED/2020/PDF/02). RSH is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished McKnight University Professor, and an Investigator of the Howard Hughes Medical Institute.

Funding Information:
These studies were supported in part by the Minnesota Ovarian Cancer Alliance (to RSH), P01-

Funding Information:
in part by a Fellowship from the Susan G. Komen

Funding Information:
was supported by the National Research Foundation Singapore and the Singapore Ministry of

Publisher Copyright:
© 2020, eLife Sciences Publications Ltd. All rights reserved.

Keywords

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

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