Fig 1.
Cellular processing of AID/A3-induced genomic uracils.
Schematic of deaminase enzymes targeting single-stranded DNA in the progressing replication fork and the fate of the genomic uracils. AID targets single-stranded DNA in transcription bubbles resulting in U:G mismatches recognized by mismatch repair (MutS; blue panel) or base excision repair (UDG; green panel). UDG excises uracil resulting in an abasic site that is cleaved by APE1. If uracils were present in close proximity and in both strands, cleavage of the DNA backbone by APE1 will induce genomic instability (purple panel). The A3 proteins target cytosines in progressing replication forks. Copying over the resulting uracil will result in a C to T transition mutation (orange panel). UDG can also travel with the replication machinery and excise the uracil, resulting in an abasic site. Abasic sites can be bypassed by translesion synthesis polymerases resulting in a C to N (any nucleotide) mutation (orange panel). Alternatively, HMCES can crosslink the abasic site (yellow panel), halting the progression of replication and protecting the DNA from strand breaks until appropriate repair machinery is recruited. AID, activation-induced cytosine deaminase; APOBEC, apolipoprotein B mRNA editing catalytic polypeptide; HMCES, 5-hydroxymethylcytosine-binding ES cell-specific protein; UDG, uracil-DNA glycosylase; APE1, apurinic/apyrimidinic endonuclease 1.
Fig 2.
Overview of DNA tumor virus antagonism of uracil-mediated antiviral immunity (UMAI).
(A) Representative schematic of successful UMAI by the AID/A3 proteins. Uracils introduced into the viral genome by the AID/A3 proteins are replicated or removed by UDG resulting in a dead or attenuated virus and viral restriction. (B) HBV’s viral protein Hbx antagonizes A3G targeting the viral cccDNA in the cytoplasm, by exosome export. Proposed A3B editing of the Hbx gene results in the carcinogenic truncated mutant and possibly genome integration. (C) KSHV vIL-6 up-regulates AID but antagonizes UMAI through viral miRNA targeting AID transcripts for degradation. KSHV also avoids UMAI by changing nuclear A3's cellular localization via its vRNR protein (ORF61). The KSHV episome may be protected from uracil accumulation during latency because it encodes for its own vUNG (ORF46) or through the tethering of the host UNG2 via LANA. (D) HPV’s oncogenic proteins E6 and E7 keep A3 expression on and inhibit degradation of A3A. It has been proposed that A3 targeting of the HPV genome leads to genome integration and viral evolution, including depletion of 5’ TC dinucleotides. (E) EBV’s EBNA3C protein up-regulates AID but may avoid uracil genotoxicity by degradation of the host UNG2 and utilizing its own vUNG protein (BKRF3). Like KSHV, EBV’s vRNR (BORF2) relocalizes nuclear A3 proteins to alternative cellular compartments. (F) MCPyV, like HPV, may utilize the nuclear A3 proteins for genome evolution and induce genome integration. A3A targeting of the large T antigen has been associated with the carcinogenic truncated protein. (G) Representative schematic of evolved viral genomes (depleted of AID/A3 target sites), which escape UMAI and facilitate tumorigenesis. The persistence of these viruses and chronic infection could lead to constitutive expression of the AID/A3 proteins giving them more opportunity to target the host genome. AID, activation-induced cytosine deaminase; cccDNA, covalently closed circular DNA; EBV, Epstein–Barr virus; KSHV, Kaposi sarcoma-associated herpesvirus; LANA, latency-associated nuclear antigen; MCPyV, Merkel cell polyomavirus; UDG, uracil-DNA glycosylase; UMAI, uracil-mediated antiviral immunity; vIL-6, viral IL-6; vRNR, viral ribonucleotide reductase large subunit; A3A, APOBEC3A; A3G, APOBEC3G.