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.
Highlights
The DNA cytosine deaminase APOBEC3B (A3B) was identified recently as a major source of mutation in cancer [1,2,3,4,5,6,7,8,9,10,11]
To determine human A3B (huA3B) sensitivity to degradation by various lentiviral Vif proteins, we tested the ability of a panel of Vif constructs derived from HIV-1IIIB, SIVmac239, bovine immunodeficiency virus (BIV), maedi-visna virus (MVV), and feline immunodeficiency virus (FIV) to mediate degradation of huA3B
The expected sizes of these Vif proteins range from approximately 23.9 kDa for HIV-1IIIB Vif to 30.4 kDa for FIV Vif including the 1.2 kDa carboxy-terminal MYC epitope tag
Summary
The DNA cytosine deaminase APOBEC3B (A3B) was identified recently as a major source of mutation in cancer [1,2,3,4,5,6,7,8,9,10,11]. A3B was initially determined to be upregulated in breast tumors, and this upregulation correlates with increased mutation loads at its preferred DNA deamination motif (i.e. 5′-TC-3′) [1] These mutations have been observed to occur in clusters, termed kataegis, and correlated with translocations and other chromosomal aberrations [6, 12, 13]. Clinical data have begun to accumulate, demonstrating that elevated A3B expression correlates with poor outcomes in breast cancer patients [14, 15] Together, these studies support a model in which A3B is a major source of mutation in cancer that drives tumor evolution, therapy resistance, and poor patient outcomes (reviewed in [16,17,18])
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