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Journal of Virology, September 1998, p. 7012-7023, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Vaccinia Virus A18R DNA Helicase Is a Postreplicative Negative Transcription Elongation Factor

Ying Xiang,1 David A. Simpson,1,dagger Jason Spiegel,1,Dagger Aimin Zhou,2 Robert H. Silverman,2 and Richard C. Condit1,*

Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610-0266,1 and Department of Cancer Biology, Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 441952

Received 16 April 1998/Accepted 21 May 1998

Loss of vaccinia virus A18R gene function results in an aberrant transcription profile termed promiscuous transcription, defined as transcription within regions of the genome which are normally transcriptionally silent late during infection. Promiscuous transcription results in an increase in the intracellular concentration of double-stranded RNA, which in turn results in activation of the cellular 2-5A pathway and subsequent RNase L-catalyzed degradation of viral and cellular RNAs. One of three hypotheses could account for promiscuous transcription: (i) reactivation of early promoters late during infection, (ii) random transcription initiation, (iii) readthrough transcription from upstream promoters. Transcriptional analysis of several viral genes, presented here, argues strongly against the first two hypotheses. We have tested the readthrough hypothesis by conducting a detailed transcriptional analysis of a region of the vaccinia virus genome which contains three early genes (M1L, M2L, and K1L) positioned directly downstream of the intermediate gene, K2L. The results show that mutation of the A18R gene results in increased readthrough transcription of the M1L gene originating from the K2L intermediate promoter. A18R mutant infection of RNase L knockout mouse fibroblast (KO3) cells does not result in 2-5A pathway activation, yet the virus mutant is defective in late viral gene expression and remains temperature sensitive. These results demonstrate that the A18R gene product is a negative transcription elongation factor for postreplicative viral genes.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610-0266. Phone: (352) 392-3128. Fax: (352) 392-3133. E-mail: condit{at}college.med.ufl.edu.

dagger Present address: Molecular Biology, Quidel Corporation, San Diego, CA 92121.

Dagger Present address: Department of Molecular Pharmacology, Memphis, TN 38105-2794.

Journal of Virology, September 1998, p. 7012-7023, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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Copyright © 1998 by the American Society for Microbiology. All rights reserved.