RNA editing plays a central role in the life cycle of hepatitis delta virus, a subviral human pathogen. A cellular protein, likely a double- stranded RNA adenosine deaminase, is responsible for editing the antigenomic RNA at the amber/W site. This process changes the function of the viral protein from one of supporting RNA replication to one of facilitating virion formation and inhibiting RNA replication. Editing is highly specific, and requires a particular structure in the HDV RNA. The long-term objectives of the proposal are to expand our understanding of RNA editing via adenosine deamination, and the particular mechanisms through which this process is utilized by HDV. Post-transcriptional regulation by adenosine deamination is increasingly recognized as an important biologic regulatory mechanism that specifically controls the expression of viral and cellular protein variants that have altered functions. The identification and characterization of the RNA structures required, the deaminase enzymes responsible for the modifications, and accessory factors that might influence editing rates and specificity, remain important goals in advancing our understanding of this process.
The specific aims are 1) to define the RNA structures required for editing HDV genotype I RNA; 2) to identify the RNA structures required for editing HDV genotype III RNA; 3) to evaluate the effects of modulating RNA adenosine deaminase expression on HDV RNA editing, RNA replication, virion formation, and genetic stability; and 4) to examine the mechanisms and implications of the inhibition of editing by hepatitis delta antigen, the sole viral protein.
These aims will be addressed by a combination of approaches, including site- directed mutagenesis, analysis in vitro of editing and RNA-protein interactions, and evaluation of editing and its consequences in transfected cells.
|Casey, John L (2012) Control of ADAR1 editing of hepatitis delta virus RNAs. Curr Top Microbiol Immunol 353:123-43|
|Chen, Renxiang; Linnstaedt, Sarah D; Casey, John L (2010) RNA editing and its control in hepatitis delta virus replication. Viruses 2:131-46|
|Lin, Brian C; Defenbaugh, Dawn A; Casey, John L (2010) Multimerization of hepatitis delta antigen is a critical determinant of RNA binding specificity. J Virol 84:1406-13|
|Defenbaugh, Dawn A; Johnson, Matthew; Chen, Renxiang et al. (2009) Hepatitis delta antigen requires a minimum length of the hepatitis delta virus unbranched rod RNA structure for binding. J Virol 83:4548-56|
|Gandy, Sharon Z; Linnstaedt, Sarah D; Muralidhar, Sumitra et al. (2007) RNA editing of the human herpesvirus 8 kaposin transcript eliminates its transforming activity and is induced during lytic replication. J Virol 81:13544-51|
|Casey, John L; Tennant, Bud C; Gerin, John L (2006) Genetic changes in hepatitis delta virus from acutely and chronically infected woodchucks. J Virol 80:6469-77|
|Casey, J L (2006) RNA editing in hepatitis delta virus. Curr Top Microbiol Immunol 307:67-89|
|Jayan, Geetha C; Casey, John L (2005) Effects of conserved RNA secondary structures on hepatitis delta virus genotype I RNA editing, replication, and virus production. J Virol 79:11187-93|
|Cheng, Qiufang; Jayan, Geetha C; Casey, John L (2003) Differential inhibition of RNA editing in hepatitis delta virus genotype III by the short and long forms of hepatitis delta antigen. J Virol 77:7786-95|
|Casey, John L (2002) RNA editing in hepatitis delta virus genotype III requires a branched double-hairpin RNA structure. J Virol 76:7385-97|
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