Earlylife is thought likely to have been RNA-based, aphase commonly referred to as 'the RNA world'. Clearly, a means must have existed that permitted these primordial RNA molecules to be copied. Today, however, RNA-dependent RNA copying is regarded as a process reserved exclusively for RNA viruses, but not cellular RNAs. Virtually all RNA viruses (except retroviruses) undergo RNA-dependent RNA replication by a virus-encoded RNA-dependent RNA polymerase (RdRp), which specifically replicates the viral RNA genome but nothing else. Even satellite viral RNAs, which do not encode their own polymerase, rely on RdRp provided by the coexisting helper virus for their replication. The exceptions to this are hepatitis delta virus (HDV) and the small infectious agents of plants, viroids, neither of which encode an RdRp. Nevertheless, they undergo robust RNA replication once inside the cells.

Increasing evidence is emerging to suggest that the ability of cells to copy RNA was not lost in antiquity after all. Most of this comes from plants and lower animal species that have been shown to encode RdRps. These RdRps could potentially be responsible for viroid replication and are also thought to be involved in gene silencing by amplifying the short pieces of RNA prepared by the dicer complex. However, very recently, results in arabidopsis suggest that these cellular RdRps may, in addition, be responsible for maintaining a novel extra-genomic cache of sequence information from generation to generation (Lolle et al. 2005).

In contrast, mammalian cells have not been shown to encode any RdRps. Thus, the mechanismofHDV RNAreplicationisstillamystery although cellular enzymes must be responsible. In this article, evidence from our and other laboratories will be reviewed that indicate that HDV RNA replication likely occurs via a redirection of host cell DNA-dependent RNA polymerases. HDV RNA replication represents the first example of RNA copying in mammalian cells; thus, the study of this system may provide a primer to the understanding of what may turn out to be a much more widespread phenomenon.

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