RNA‐dependent RNA polymerase, RdRP, a promising therapeutic target for cancer and potentially COVID‐19. Issue 11 (12th September 2020) - Machitani, Mitsuhiro
Abstract: A recent outbreak of coronavirus disease (COVID‐19) caused by the novel severe acute respiratory syndrome coronavirus 2 has driven a global pandemic with catastrophic consequences. The rapid development of promising therapeutic strategies against COVID‐19 is keenly anticipated. Family Coronaviridae comprises positive, single‐stranded RNA viruses that use RNA‐dependent RNA polymerase (RdRP) for viral replication and transcription. As the RdRP of viruses in this family and others plays a pivotal role in infection, it is a promising therapeutic target for developing antiviral agents against them. A critical genetic driver for many cancers is the catalytic subunit of telomerase: human telomerase reverse transcriptase (hTERT), identified initially as an RNA‐dependent DNA polymerase. However, even though hTERT is a DNA polymerase, it has phylogenetic and structural similarities to viral RdRPs. Researchers worldwide, including the authors of this review, are engaged in developing therapeutic strategies targeting hTERT. We have published a series of papers reporting that hTERT has RdRP activity and that this RdRP activity in hTERT is essential for tumor formation. Here, we review the enzymatic function of RdRP in virus proliferation and tumor development, reminding us of how the study of the novel coronavirus has brought us to the unexpected intersection of cancer research and RNA virus research. Abstract : In cancer cells, human telomerase reverse transcriptase (hTERT) is phosphorylated by cyclin‐dependent kinase 1 (CDK1), and the phosphorylated hTERT shows RNA‐dependent RNA polymerase (RdRP) activity. The phosphorylated hTERT regulates the expression of target genes, leading to tumor progression. After the entry of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) into the cell, the RdRP plays a role in transcription and replication of viral RNAs. The inhibition of RdRP activity is a promising molecular target for cancer and SARS‐CoV‐2 infection.