Research advances in the role of RNA m5C in viral replication

ABSTRACT

It is well-known that RNA is the target of numerous chemical modifications which currently amount to over a hundred. Among them, 5-methylcytosine (m5C) is a prevalent RNA modification in multiple eukaryotic RNA species, such as messenger RNAs (mRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), vault RNAs (vtRNAs), long non-coding RNAs (lncRNAs) and enhancer RNAs (eRNAs). In recent years, several techniques for detecting m5C have been developed, including UPLC-MS/MS, m5C-MeRIP-seq, PA-m5C-seq, RNA-BisSeq and nanopore sequencing. The rapid development of these high-throughput techniques sharply facilitates the in-depth studies of the biological functions of m5C. The m5C modification is enriched around start codon along mRNAs and conserved in tRNAs and rRNAs. It is a reversible RNA modification catalyzed by methyltransferases (NSUN, DNMT, and TRDMT family members) and removed by demethylases (TET family members and ALKBH1). The m5C modification can be recognized by a set of RNA-binding proteins (YBX family members, ALYREF and FMRP) and is widely involved in the regulation of RNA metabolic processes, including nuclear export, stability and translation. In addition, the dysregulation of m5C modification is closely related with the defect of DNA repair, cell proliferation, embryonic development and stem cell differentiation. Viruses are infectious agents that rely on host cells for replication. They have evolved numerous strategies to shape the cellular biosynthesis and metabolism machinery of hosts to complete their life cycle and propagate. One strategy is to modify viral RNAs using host m5C RNA methyltransferases (NSUN1, NSUN2, NSUN5 and DNMT2), and thus directly regulates their transcription, splicing and translation. So far, combined with the high-throughput techniques, some viral m5C landscapes have been precisely depicted, including human immunodeficiency virus type (HIV-1), murine leukemia virus (MLV), Epstein-Barr virus (EBV), and so on. Studies showed that the m5C level of retroviral mRNAs is much higher than cellular mRNAs, suggesting this modification can be a special marker for host cells to distinguish “self” and “non-self”. In addition, the m5C methylome of cellular RNAs is dynamically regulated under viral infection, leading to the suppression of host innate immunity. Therefore, it will be of great significance in the design and development of novel antiviral drugs by systemically understanding the molecular mechanisms of m5C modification in controlling viral replication and host innate immunity. In this review, the latest findings of m5C methyltransferases, demethylases, reader proteins and high-throughput sequencing techniques are presented. We discuss how m5C modification is catalyzed and recognized on viral RNAs of retrovirus, DNA virus, flavivirus and coronavirus. Furthermore, we summarize the roles of RNA m5C modification in viral replications and host innate immunity. This review will provide some valuable information for understanding the epigenetics in viral RNAs. © 2022 Chinese Academy of Sciences. All rights reserved.