Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands
Chai Yeen Goh
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
Boon Haow Chua
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Matthew C Jarvis
Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States
Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Mater Research Institute, The University of Queensland, Faculty of Medicine, Brisbane, Australia
Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, United States
Rebecca M McDougle
Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Hennepin Healthcare, Minneapolis, United States
Michael A Carpenter
Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, United States
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, United States
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 the binding of wildtype but not mutant E2F promoters by repressive PRC1.6/E2F6 and DREAM/E2F4 complexes. Knockdown and overexpression studies confirm the 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.
