Degradation of the cancer genomic DNA deaminase APOBEC3B by SIV Vif

// Allison M. Land 1, 2 , Jiayi Wang 1 , Emily K. Law 1 , Ryan Aberle 1 , Andrea Kirmaier 3 , Annabel Krupp 3, 4 , Welkin E. Johnson 3 , Reuben S. Harris 1 1 Department of Biochemistry, Molecular Biology and Biophysics, Institute for Molecular Virology, Masonic Cancer Center, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, USA 2 Present address: Department of Biological Sciences, Minnesota State University Mankato, Mankato, Minnesota, USA 3 Department of Biology, Boston College, Boston, Massachusetts, USA 4 Present address: Biogen Idec, Cambridge, Massachusetts, USA Correspondence to: Reuben S. Harris, e-mail: rsh@umn.edu Keywords: APOBEC3B, cancer mutagenesis, endogenous DNA deamination, lentiviral Vif, tumor evolution Received: June 07, 2015      Accepted: October 19, 2015      Published: October 31, 2015 ABSTRACT APOBEC3B is a newly identified source of mutation in many cancers, including breast, head/neck, lung, bladder, cervical, and ovarian. APOBEC3B is a member of the APOBEC3 family of enzymes that deaminate DNA cytosine to produce the pro-mutagenic lesion, uracil. Several APOBEC3 family members function to restrict virus replication. For instance, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H combine to restrict HIV-1 in human lymphocytes. HIV-1 counteracts these APOBEC3s with the viral protein Vif, which targets the relevant APOBEC3s for proteasomal degradation. While APOBEC3B does not restrict HIV-1 and is not targeted by HIV-1 Vif in CD4-positive T cells, we asked whether related lentiviral Vif proteins could degrade APOBEC3B. Interestingly, several SIV Vif proteins are capable of promoting APOBEC3B degradation, with SIVmac239 Vif proving the most potent. This likely occurs through the canonical polyubiquitination mechanism as APOBEC3B protein levels are restored by MG132 treatment and by altering a conserved E3 ligase-binding motif. We further show that SIVmac239 Vif can prevent APOBEC3B mediated geno/cytotoxicity and degrade endogenous APOBEC3B in several cancer cell lines. Our data indicate that the APOBEC3B degradation potential of SIV Vif is an effective tool for neutralizing the cancer genomic DNA deaminase APOBEC3B. Further optimization of this natural APOBEC3 antagonist may benefit cancer therapy.