Restriction of Editing to the AmberW Site

ADAR1 and ADAR2 can extensively edit long (> 50 base-pairs) double-stranded RNAs, in which up to 50% of adenosines maybe deaminated. Clearly, promiscuous editing such as occurs on dsRNA could be deleterious to virus replication. Indeed, spurious editing on HDV RNA by overexpressed ADAR1

and ADAR2 led to the production of protein variants that inhibited replication (Jayan and Casey 2002a). However, even though HDV RNA exhibits significant base-pairing in the unbranched rod structure, promiscuous editing does not typically occur during HDV infection; the amber/W site is edited 600-fold more efficiently than the other 337 adenosines in the RNA (Polson et al. 1998). It is worth noting here that, although editing at nonamber/W sites does not appear to occur at levels important for the replication cycle, the genetic evolution of the virus may nevertheless be affected by ADAR editing during the course of infection (see the chapter by J.L. Casey and J.L. Gerin, this volume). It is likely that the primary and secondary structure of the HDV RNA have evolved to avoid undesirable (for the virus) editing at sites other than amber/W. As noted in Sect. 3, analysis of editing on dsRNAs has indicated that adenosines with a 5' guanosine neighbor are much less likely to be deaminated than other adenosines (Polson and Bass 1994). In both the HDV genome and antigenome, guanosine is by far the most common 5' neighbor for adenosine, and the ratios of observed to expected occurrences for the dinucleotides GA and UC (which would be GA in the complementary strand) are higher than for any other dinucleotides. This bias may be due, in part, to selection for sequences that place nonamber/W adenosines in contexts that are less likely to be edited. As for secondary structure, base-pairing in the HDV RNA unbranched rod structure is interrupted by frequent bulges, internal loops and mismatches, which have been shown to restrict editing on artificial dsRNA substrates (Aruscavage and Bass 2000; Lehmann and Bass 1999; Ohman et al. 2000).

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