Oncotarget

Priority Research Papers:

Human cytomegalovirus and Herpes Simplex type I virus can engage RNA polymerase I for transcription of immediate early genes

Ourania N. Kostopoulou, Vanessa Wilhelmi, Sina Raiss, Sharan Ananthaseshan, Mikael S. Lindström, Jiri Bartek, Cecilia Söderberg-Naucler _

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Oncotarget. 2017; 8:96536-96552. https://doi.org/10.18632/oncotarget.22106

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Abstract

Ourania N. Kostopoulou1,*, Vanessa Wilhelmi1,*, Sina Raiss1, Sharan Ananthaseshan1, Mikael S. Lindström2, Jiri Bartek2 and Cecilia Söderberg-Naucler1

1 Department of Medicine, Center for Molecular Medicine L8:03, Karolinska University Hospital, Stockholm, Sweden

2 Department of Medical Biochemistry and Biophysics, Science For Life Laboratory, Division of Genome Biology, Karolinska Institute, Solna, Sweden

* These authors have contributed equally to this study

Correspondence to:

Cecilia Söderberg-Naucler, email:

Jiri Bartek, email:

Keywords: cytomegalovirus; replication; RNA Polymerase I; Herpes Simplex type 1 virus; nucleolus

Received: July 18, 2017 Accepted: October 13, 2017 Published: October 29, 2017

Abstract

Human cytomegalovirus (HCMV) utilizes RNA polymerase II to transcribe viral genes and produce viral mRNAs. It can specifically target the nucleolus to facilitate viral transcription and translation. As RNA polymerase I (Pol I)-mediated transcription is active in the nucleolus, we investigated the role of Pol I, along with relative contributions of the human Pol II and Pol III, to early phases of viral transcription in HCMV infected cells, compared with Herpes Simplex Virus-1 (HSV-1) and Murine cytomegalovirus (MCMV). Inhibition of Pol I with siRNA or the Pol I inhibitors CX-5461 or Actinomycin D (5nM) resulted in significantly decreased IE and pp65 mRNA and protein levels in human fibroblasts at early times post infection. This initially delayed replication was compensated for later during the replication process, at which stage it didn’t significantly affect virus production. Pol I inhibition also reduced HSV-1 ICP0 and gB transcripts, suggesting that some herpesviruses engage Pol I for their early transcription. In contrast, inhibition of Pol I failed to affect MCMV transcription. Collectively, our results contribute to better understanding of the functional interplay between RNA Pol I-mediated nucleolar events and the Herpes viruses, particularly HCMV whose pathogenic impact ranges from congenital malformations and potentially deadly infections among immunosuppressed patients, up to HCMV’s emerging oncomodulatory role in human tumors.


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