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Molecular and Cellular Biology, August 2000, p. 6030-6039, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

RNA-Dependent Replication and Transcription of Hepatitis Delta Virus RNA Involve Distinct Cellular RNA Polymerases

Lucy E. Modahl,1 Thomas B. Macnaughton,1 Nongliao Zhu,1 Deborah L. Johnson,2 and Michael M. C. Lai1,3,*

Howard Hughes Medical Institute3 and Departments of Molecular Microbiology and Immunology1 and Molecular Pharmacology and Toxicology,2 Schools of Medicine and Pharmacy, University of Southern California, Los Angeles, California 90033

Received 3 January 2000/Returned for modification 7 February 2000/Accepted 20 May 2000

Cellular DNA-dependent RNA polymerase II (pol II) has been postulated to carry out RNA-dependent RNA replication and transcription of hepatitis delta virus (HDV) RNA, generating a full-length (1.7-kb) RNA genome and a subgenomic-length (0.8-kb) mRNA. However, the supporting evidence for this hypothesis was ambiguous because the previous experiments relied on DNA-templated transcription to initiate HDV RNA synthesis. Furthermore, there is no evidence that the same cellular enzyme is involved in the synthesis of both RNA species. In this study, we used a novel HDV RNA-based transfection approach, devoid of any artificial HDV cDNA intermediates, to determine the enzymatic and metabolic requirements for the synthesis of these two RNA species. We showed that HDV subgenomic mRNA transcription was inhibited by a low concentration of alpha -amanitin (<3 µg/ml) and could be partially restored by an alpha -amanitin-resistant mutant pol II; however, surprisingly, the synthesis of the full-length (1.7-kb) antigenomic RNA was not affected by alpha -amanitin to a concentration higher than 25 µg/ml. By several other criteria, such as the differing requirement for the de novo-synthesized hepatitis delta antigen and temperature dependence, we further showed that the metabolic requirements of subgenomic HDV mRNA synthesis are different from those for the synthesis of genomic-length HDV RNA and cellular pol II transcripts. The synthesis of the two HDV RNA species could also be uncoupled under several different conditions. These findings provide strong evidence that pol II, or proteins derived from pol II transcripts, is involved in mRNA transcription from the HDV RNA template. In contrast, the synthesis of the 1.7-kb HDV antigenomic RNA appears not to be dependent on pol II. These results reveal that there are distinct molecular mechanisms for the synthesis of these two RNA species.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 401, Los Angeles, CA 90033. Phone: (323) 442-1748. Fax: (323) 342-9555. E-mail: michlai{at}hsc.usc.edu.

Molecular and Cellular Biology, August 2000, p. 6030-6039, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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