Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022:112:87-114.
doi: 10.1016/bs.aivir.2022.01.002. Epub 2022 Mar 7.

Control of animal virus replication by RNA adenosine methylation

Angus C Wilson  1 , Ian Mohr  2
Affiliations
Review

Control of animal virus replication by RNA adenosine methylation

Angus C Wilson et al. Adv Virus Res. 2022.

Abstract

Methylation at the N6-position of either adenosine (m6A) or 2'-O-methyladenosine (m6Am) represents two of the most abundant internal modifications of coding and non-coding RNAs, influencing their maturation, stability and function. Additionally, although less abundant and less well-studied, monomethylation at the N1-position (m1A) can have profound effects on RNA folding. It has been known for several decades that RNAs produced by both DNA and RNA viruses can be m6A/m6Am modified and the list continues to broaden through advances in detection technologies and identification of the relevant methyltransferases. Recent studies have uncovered varied mechanisms used by viruses to manipulate the m6A pathway in particular, either to enhance virus replication or to antagonize host antiviral defenses. As such, RNA modifications represent an important frontier of exploration in the broader realm of virus-host interactions, and this new knowledge already suggests exciting opportunities for therapeutic intervention. In this review we summarize the principal mechanisms by which m6A/m6Am can promote or hinder viral replication, describe how the pathway is actively manipulated by biomedically important viruses, and highlight some remaining gaps in understanding how adenosine methylation of RNA controls viral replication and pathogenesis.

Keywords: Epitranscriptomic regulation; N(1)-methyladenosine; N(6),2′-O-methyladenosine; N(6)-methyladenosine; RNA modification; Virus–host interactions.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Reversible conversion of adenosine in RNA to m6A, m6Am and m1A. (A) N6-methyladenosine (m6A) is the most abundant internal modification of both mRNA and lncRNA in mammalian cells and is catalyzed by a core writer complex composed of METTL3, METTL14 and WTAP. m6A-modified RNAs can be recognized by a variety of RNA binding proteins (readers), several of which contain a YTH domain. Demethylation is mediated by the ALKBH5 and FTO eraser proteins, although as indicated by the question mark the full extent and relative contribution of FTO in particular, remain uncertain. (B) N6-methylation of cap-adjacent N6,2′-O-dimethyladenosine (m6Am) is catalyzed by PCIF1 (also known as CAPAM) (Akichika et al., 2019). Methylation of the 2′-O-ribose of the first and second transcribed nucleotides is catalyzed by hMTr1 and hMTr2, respectively (Bélanger et al., 2010; Werner et al., 2011). The enzymes responsible for installation of m6A away from the cap structures are less well understood, however internal m6Am methylation of U2 small nuclear RNA (snRNA) is catalyzed by METTL4 at sites of pre-deposited 2’-O-methylation (H. Chen et al., 2020). Note that demethylation of m6Am by FTO generates 2′-O-methyladenosine and it is unclear if or how this can be further converted to the unmethylated ribonucleotide. Specific readers of m6Am have yet to be identified but conceivably they include known m6A readers. (C) Additionally, adenosine can also be monomethylated at the N1 position (m1A) which interferes with the Watson-Crick interface and introduces a positive charge under physiological conditions that together can alter RNA secondary structure. Enzymes including TRMT6/61A, TRMT61B, and TRMT10C have been implicated as m1A writers (Li et al., 2017; Safra et al., 2017), with ALKBH1 and ALKBH3 identified as the erasers (Dominissini et al., 2016; Li et al., 2016). There is evidence that YTHDF1-YTHDF3 and YTHDC1 can act as m1A readers potentially complicating the interpretation of reader depletion studies (Dai et al., 2018; Seo and Kleiner, 2020).
Fig. 2
Fig. 2
Viruses manipulate the m6A pathway at multiple steps to effect changes in RNA function or fate. During RNA polymerase II (RNAPII) transcription, m6A (red dot) is installed on nascent transcripts by a polymerase-associated complex that includes the essential METTL3 and METTL14 subunits, and is potentially reversed through the actions of the nuclear demethylase ALKBH5. The m6A epitranscriptomic mark is recognized by reader proteins such as YTHDC1 to influence splicing and/or facilitate export into the cytoplasm. Of special relevance to viral infections, the expression of the unspliced IFNβ1 mRNA (inset) is modulated by the competing inhibitory and stimulating activities of METTL3/14 and ALKBH5, respectively. Once in the cytoplasm, m6A-modified polyadenylated RNAs engage with a variety of other reader proteins that recognize m6A directly or indirectly and influence transcript function and fate. Depending on the cell type and possibly the site and density of m6A installation, the binding of YTHDF2 can destabilize mRNAs through polyA tail shortening by the CCR4/NOT complex. Alternatively readers can confer increased stability or can stimulate translation by ribosomes. RNA folding can also be modulated through the presence or absence of m6A and this can limit recognition of virus RNA signatures by innate defense sensors such as RIG-I or MDA5. Many of these steps are manipulated by viruses during infection either to enhance their own gene expression and/or genome replication or to suppress antiviral activities. Here representative viruses that stimulate or upregulate host m6A-associated functions are identified in green, whereas those that repress host functions are shown in red. See text for more discussion.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Akichika S, et al., 2019. Cap-specific terminal N6-methylation of RNA by an RNA polymerase II-associated methyltransferase. Science (New York, NY) 363 (6423), eaav0080. 10.1126/science.aav0080. - DOI - PubMed
    1. Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF, 2015. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162 (6), 1299–1308. 10.1016/j.cell.2015.08.011. - DOI - PMC - PubMed
    1. Alarcón CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF, 2015. N6-methyladenosine marks primary microRNAs for processing. Nature 519 (7544), 482–485. 10.1038/nature14281. - DOI - PMC - PubMed
    1. Baquero-Perez B, Antanaviciute A, Yonchev ID, Carr IM, Wilson SA, Whitehouse A, 2019. The Tudor SND1 protein is an m6A RNA reader essential for replication of Kaposi’s sarcoma-associated herpesvirus. eLife 8, 482. 10.7554/elife.47261. - DOI - PMC - PubMed
    1. Barbieri I, Kouzarides T, 2020. Role of RNA modifications in cancer. Nature Reviews Cancer 20 (6), 303–322. 10.1038/s41568-020-0253-2. - DOI - PubMed