Abstract
Retroviruses, hepadnaviruses, and some other retroelements are vulnerable to editing by single stranded DNA cytidine deaminases. Of the eleven human genes encoding such enzymes, eight have demonstrable enzymatic activity. Six of seven human APOBEC3 are able to hyperedit HBV DNA, frequently on both strands. Although human APOBEC1 (hA1) is not generally expressed in normal liver, hA1 can edit single stranded DNA in a variety of experimental assays. The possibility of ectopic expression of hA1 in vivo cannot be ruled out and interestingly, transgenic mice with A1 expressed under a liver specific promoter develop hepatocellular carcinoma. The impact of hA1 on HBV in tissue culture is varied with reports noting either reduced DNA synthesis or not, with cytidine deamination taking a low profile. We sought to examine the hA1 editing activity on replicating HBV. Using highly sensitive 3DPCR it was possible to show that hA1 edits the HBV minus DNA strand as efficiently as hA3G, considered the reference deaminase for HIV and HBV. The dinucleotide specificity of editing was unique among human cytidine deaminases providing a hallmark of use in a posteriori analyses of in vivo edited genomes. Analysis of sequences derived from the serum of two chronic carriers, indicated that hA1 explained only a small fraction of edited HBV genomes. By contrast, several human APOBEC3 deaminases were active including hA3G.
Highlights
Human A1 edits a single cytidine residue in human apolipoprotein B mRNA, a specificity that is conferred by its major interactor, APOBEC1 complementary factor (ACF), its expression being confined to intestinal epithelial cells [4,5]
For transgenic mice expressing the rabbit APOBEC1 gene under the control of a liver specific promoter, hepatic dysplasia and hepatocellular carcinomas were found [12]. Whether this is due to RNA or DNA editing is unknown in an E. coli DNA mutator assay, human APOBEC1 (hA1) was highly mutagenic meaning that the latter cannot be ruled out [13]
An infectious molecular clone of hepatitis B virus (HBV) was transfected into quail QT6 cells with hA1 along with human APOBEC2 and human APOBEC3G as negative and positive controls
Summary
Another study shows that the rat A1 deaminase hardly impacts HBV replication, even though a little cytidine deamination was found [30]. An infectious molecular clone of HBV was transfected into quail QT6 cells with hA1 along with human APOBEC2 (hA2) and human APOBEC3G (hA3G) as negative and positive controls. Using SYBR green quantification of HBV DNA, when normalized to the empty expression vector transfection control, hA1 and hA3G clearly impacted DNA replication (Figure 1B).
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