1. Academic Validation
  2. Targeting the m6A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

Targeting the m6A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

  • Genes Dev. 2021 Jul 1;35(13-14):1005-1019. doi: 10.1101/gad.348320.121.
Hannah M Burgess 1 Daniel P Depledge 2 Letitia Thompson 1 Kalanghad Puthankalam Srinivas 1 Rebecca C Grande 1 Elizabeth I Vink 1 Jonathan S Abebe 2 Wesley P Blackaby 3 Alan Hendrick 3 Mark R Albertella 3 Tony Kouzarides 4 Kenneth A Stapleford 1 Angus C Wilson 1 Ian Mohr 1
Affiliations

Affiliations

  • 1 Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
  • 2 Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
  • 3 Storm Therapeutics Ltd, Cambridge CB22 3AT, United Kingdom.
  • 4 The Gurdon Institute, Department of Pathology, University of Cambridge, Cambridge CB2 1QN, United Kingdom.
Abstract

N6-methyladenosine (m6A) is an abundant internal RNA modification, influencing transcript fate and function in uninfected and virus-infected cells. Installation of m6A by the nuclear RNA methyltransferase METTL3 occurs cotranscriptionally; however, the genomes of some cytoplasmic RNA viruses are also m6A-modified. How the cellular m6A modification machinery impacts coronavirus replication, which occurs exclusively in the cytoplasm, is unknown. Here we show that replication of SARS-CoV-2, the agent responsible for the COVID-19 pandemic, and a seasonal human β-coronavirus HCoV-OC43, can be suppressed by depletion of METTL3 or cytoplasmic m6A reader proteins YTHDF1 and YTHDF3 and by a highly specific small molecule METTL3 Inhibitor. Reduction of infectious titer correlates with decreased synthesis of viral RNAs and the essential nucleocapsid (N) protein. Sites of m6A modification on genomic and subgenomic RNAs of both viruses were mapped by methylated RNA immunoprecipitation Sequencing (meRIP-seq). Levels of host factors involved in m6A installation, removal, and recognition were unchanged by HCoV-OC43 infection; however, nuclear localization of METTL3 and cytoplasmic m6A readers YTHDF1 and YTHDF2 increased. This establishes that coronavirus RNAs are m6A-modified and host m6A pathway components control β-coronavirus replication. Moreover, it illustrates the therapeutic potential of targeting the m6A pathway to restrict coronavirus reproduction.

Keywords

HCoV-OC43; N6-methyladenosine; RNA modification; SARS-CoV-2; coronavirus; direct RNA sequencing; nanopore sequencing; virus–host interactions.

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