Abstract
BackgroundN6-methyladenosine (m6A) modification is the most prevalent internal modification of eukaryotic mRNA modulating gene expression. m6A modification is a dynamic reversible process regulated by three protein groups: methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). m6A modification is involved in all phases of RNA metabolism, including RNA folding, stability, splicing, nuclear exporting, translational modulation and degradation.Main bodyIn recent years, numerous studies have reported that abnormal m6A modification causes aberrant expression of important viral genes. Herein, we review the role of m6A in viral lifecycle and its contribution to the pathogenesis of human diseases. Particularly, we focus on the viruses associated with human diseases such as HIV-1, IAV, HBV, HCV, EBV and many others.ConclusionsA better understanding of m6A-virus relationship would provide new insights into the viral replication process and pathogenesis of human diseases caused by viruses. In addition, exploration of the role of m6A in disease-causing viruses will reveal novel approaches for the treatment of such diseases.
Highlights
Accumulating evidence shows that m6A modification exists in eukaryotic cells and in viruses
A recent study [14] identified a new component of writers methyltransferase-like 16 (METTL16), which is independent from the methyltransferase-like 3 (METTL3)/ methyltransferaselike 14 (METTL14)/Wilms’ tumor 1-associating protein (WTAP) complex, that caused m6A deposition on U6 snRNA [20] and U6-like hairpins of MAT2A Messenger RNA (mRNA) [21] in a C-m6A-G context
It is known that deregulation of m6A modification is associated with diseases caused by pathogenic viruses. m6A has long been identified in RNA transcripts of viruses and it regulates nuclear replication in viruses such as influenza A virus, simian virus 40, Rous sarcoma virus, avian sarcoma virus, and adenovirus [35,36,37,38]
Summary
The viruses described in this review are harmful to human health. Some viruses RNA undergo m6A modification such as Rous sarcoma virus (RSV) [79], vesicular stomatitis virus (VSV) [80], and adenoviruses [37], and are less pathogenic in human. Several advances have been made in understanding human pathogenic viruses in recent years, only few drugs for these diseases have been put on the market in the past decades. For this reason, it is necessary to focus on the development of new treatments that may replace or improve the standard therapies. Before the m6A modification-related regulatory genes and proteins can be used as prognostic and diagnostic markers for some viral diseases, studies are needed to explore the specificity and targeting precision of these molecules. Abbreviations 3’UTR: 3’untranslated region; 5’UTR: 5’untranslated region; AIDS: acquired immunodeficiency syndrome; ALKBH5: alkB homologue 5; CC: Cervical cancer; co-IP: co-immunoprecipitation; CSCC: cervical squamous cell carcinoma; DAA: 3-deazaadenosine; DFS: disease-free survival; EBV: Epstein– Barr virus; ERCC1: excision repair cross-complementation group 1; EV71: Enterovirus 71; FTO: fat mass and obesity-associated proteins; HBV: Hepatitis B virus; HCC: Hepatocellular Carcinoma; HCV: Hepatitis C virus; HIV-1: Human immunodeficiency virus I; HPV: Human papillomavirus; IAV: Influenza A virus; IGF2BPs: the insulin-like growth factor 2 mRNA-binding proteins; KS: Kaposi’s sarcoma; KSHV: Kaposi’s sarcoma-associated herpesvirus; m6A: N6-methyladenosine; m6Am: N6,2′-O-dimethyladenosine; m6Aseq: high-throughput RNA sequencing; MCD: multicentric Castleman’s disease; MeRIP-seq: methylated RNA immunoprecipitation sequening; METTL14: methyltransferase-like 14; METTL16: methyltransferase-like 16; METTL3: methyltransferase-like 3; miR126: microRNA126; mRNA: messenger RNA; MT: methyltransferase; ORF50: Open reading frame 50; OS: overall survival; PA-m6A-seq: photo-crosslinking-assisted m6A sequencing; PARCLIP: photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation; PEL: primary effusion lymphoma; RBM15: RNA binding motif protein 15; RdRp: RNA-dependent RNA polymerase; RRE: Rev response element; rRNA: ribosomal RNA; RSV: Rous sarcoma virus; RTA: replication transcription activator; SOCS2: suppressors of cytokine signaling 2; SV40: Simian Virus 40; tRNA: transfer RNA; VSV: vesicular stomatitis virus; WTAP: Wilms’ tumor 1-associating protein; ZIKV: Zika virus; ZVD: Zika virus disease
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