An epigenetic 'extreme makeover': the methylation of flaviviral RNA (and beyond)

RNA Biol. 2021 May;18(5):696-708. doi: 10.1080/15476286.2020.1868150. Epub 2021 Jan 18.

Abstract

Beyond their high clinical relevance worldwide, flaviviruses (comprising dengue and Zika viruses) are of particular interest to understand the spatiotemporal control of RNA metabolism. Indeed, their positive single-stranded viral RNA genome (vRNA) undergoes in the cytoplasm replication, translation and encapsidation, three steps of the flavivirus life cycle that are coordinated through a fine-tuned equilibrium. Over the last years, RNA methylation has emerged as a powerful mechanism to regulate messenger RNA metabolism at the posttranscriptional level. Not surprisingly, flaviviruses exploit RNA epigenetic strategies to control crucial steps of their replication cycle as well as to evade sensing by the innate immune system. This review summarizes the current knowledge about vRNA methylation events and their impacts on flavivirus replication and pathogenesis. We also address the important challenges that the field of epitranscriptomics faces in reliably and accurately identifying RNA methylation sites, which should be considered in future studies on viral RNA modifications.

Keywords: 2ʹ-O-methylation; Flavivirus; N6-methyladenosine; RNA methylation; RNA modification; West Nile virus; Zika virus; cap; dengue virus; viral RNA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Epigenesis, Genetic / physiology*
  • Flavivirus / genetics*
  • Flavivirus / metabolism
  • Flavivirus / pathogenicity
  • Genome, Viral
  • Humans
  • Methylation
  • RNA, Viral / genetics*
  • RNA, Viral / metabolism
  • Virus Replication / genetics
  • Zika Virus / genetics
  • Zika Virus / metabolism
  • Zika Virus Infection / genetics
  • Zika Virus Infection / virology

Substances

  • RNA, Viral

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft[240245660 – SFB 1129; 278001972; SPP1784, HE3397/13-2; HE3397/14-2]; ; Fonds de Recherche du Québec - Nature et Technologies [2018-NC-205593]; Fonds de Recherche du Québec - Santé; Natural Sciences and Engineering Research Council of Canada [RGPIN-2016-05584].