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RNR-R2 Upregulation by a Short Non-Coding Viral Transcript

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY 10065, USA
Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Peter Boag
Biomolecules 2021, 11(12), 1822;
Received: 14 November 2021 / Revised: 29 November 2021 / Accepted: 1 December 2021 / Published: 3 December 2021
DNA viruses require dNTPs for replication and have developed different strategies to increase intracellular dNTP pools. Hepatitis B virus (HBV) infects non-dividing cells in which dNTPs are scarce and the question is how viral replication takes place. Previously we reported that the virus induces the DNA damage response (DDR) pathway culminating in RNR-R2 expression and the generation of an active RNR holoenzyme, the key regulator of dNTP levels, leading to an increase in dNTPs. How the virus induces DDR and RNR-R2 upregulation is not completely known. The viral HBx open reading frame (ORF) was believed to trigger this pathway. Unexpectedly, however, we report here that the production of HBx protein is dispensable. We found that a small conserved region of 125 bases within the HBx ORF is sufficient to upregulate RNR-R2 expression in growth-arrested HepG2 cells and primary human hepatocytes. The observed HBV mRNA embedded regulatory element is named ERE. ERE in isolation is sufficient to activate the ATR-Chk1-E2F1-RNR-R2 DDR pathway. These findings demonstrate a non-coding function of HBV transcripts to support its propagation in non-cycling cells. View Full-Text
Keywords: deoxynucleotides and DNA viruses; RNR-R2 regulation; non-coding RNA; Hepatitis B virus deoxynucleotides and DNA viruses; RNR-R2 regulation; non-coding RNA; Hepatitis B virus
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MDPI and ACS Style

Broennimann, K.; Ricardo-Lax, I.; Adler, J.; Michailidis, E.; de Jong, Y.P.; Reuven, N.; Shaul, Y. RNR-R2 Upregulation by a Short Non-Coding Viral Transcript. Biomolecules 2021, 11, 1822.

AMA Style

Broennimann K, Ricardo-Lax I, Adler J, Michailidis E, de Jong YP, Reuven N, Shaul Y. RNR-R2 Upregulation by a Short Non-Coding Viral Transcript. Biomolecules. 2021; 11(12):1822.

Chicago/Turabian Style

Broennimann, Karin, Inna Ricardo-Lax, Julia Adler, Eleftherios Michailidis, Ype P. de Jong, Nina Reuven, and Yosef Shaul. 2021. "RNR-R2 Upregulation by a Short Non-Coding Viral Transcript" Biomolecules 11, no. 12: 1822.

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