The functions of RNA N6-methyladenosine in the nucleus

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Abstract

N6-methyladenosine (m6A) is one of the most abundant modifications of both eukaryotic and prokaryotic mRNAs. Recent years witnessed an accumulation of a large volume of experimental data on the involvement of m6A methylation in the regulation of stability and translation of different mRNAs. Remarkably, up until recently, the majority of such m6A-related studies have been focused on cytoplasmic functions of this modification. In this review, we overview a number of novel studies revealing the role of m6A in several key biological processes occurring in cellular nucleus, such as transcription, organization of chromatin, splicing, nuclear-cytoplasmic transport, and R-loop metabolism. Based on this analysis, we propose a model where modifications present on nuclear RNAs represent an additional layer of regulation of gene expression, that, together with DNA methylation and histone modifications, determines chromatin structure and function in various biological contexts.

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About the authors

N. A. Zhigalova

Research Center of Biotechnology of the Russian Academy of Sciences

Email: ermakov99@mail.ru

Institute of Bioengineering

Russian Federation, 119071 Moscow

K. Yu. Oleynikova

Research Center of Biotechnology of the Russian Academy of Sciences

Email: ermakov99@mail.ru

Institute of Bioengineering

Russian Federation, 119071 Moscow

A. S. Ruzov

Research Center of Biotechnology of the Russian Academy of Sciences

Email: ermakov99@mail.ru

Institute of Bioengineering

Russian Federation, 119071 Moscow

A. S. Ermakov

Research Center of Biotechnology of the Russian Academy of Sciences; Lomonosov Moscow State University

Author for correspondence.
Email: ermakov99@mail.ru

Institute of Bioengineering, Faculty of Biology

Russian Federation, 119071 Moscow; 119991 Moscow

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2. Fig. 1. Scheme illustrating the role of proteins involved in the regulation of m6A levels and interpreting this modification in eukaryotic cells. Adenosine methylation is performed by the methyltransferase complex consisting of METTL3, METTL14, and the WTAP protein. WTAP can also interact with other methyltransferases (“writers”): RBM15/15b, ZC3Y13, VIRMA. Demethylases or “erasers” ALKBH5 and FTO remove m6A from mRNA. In the nucleus and cytoplasm, m6A RNA can be recognized and regulated by various “readers”: proteins of the YTH family (YTHDC1, YTHDF1-3), the HNRNP family (HNRNPC, HNRNPG, and HNRNPA2B1), and IGF2BP1-3 factors.

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3. Fig. 2. Functional roles of m6A in the cell nucleus. a – m6A regulates pre-mRNA splicing. Binding of YTHDC1 to m6A results in exon excision by blocking binding of the splicing factor SRSF10 to pre-mRNA. In the absence of adenosine N6-methylation, SRSF10 binds to pre-mRNA, resulting in exon skipping. b – Adenosine N6-methylation promotes mRNA nuclear export via interaction of YTHDC1 with the SRSF3/NXF1 protein complex; in turn, the TREX complex can recruit methyltransferases to adenine methylation sites in mRNA. c – m6A can both enhance degradation of various mRNAs and stabilize them. YTHDF2 promotes the degradation of m6A-modified transcripts by recruiting the CCR4–NOT1 deadenylase complex to the target mRNA. In turn, IGF2BP (insulin-like growth factor 2 mRNA binding protein) binds to m6A-containing mRNAs and, conversely, protects them from degradation

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4. Fig. 3. The role of m6A in the organization of chromatin structure. a – m6A regulates the activity and conformation of long non-coding RNAs (lncRNAs). Xist lncRNA contains N6-adenosine, which, through an RBM15/15b-YTHDC1-dependent mechanism, promotes Xist-mediated gene repression and X-chromosome inactivation. b – YTHDC1 can bind both m6A-modified transcripts and histone H3 lysine 9 demethylase (H3K9), KDM3B, leading to histone demethylation and increased chromatin accessibility in actively transcribed regions.

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5. Fig. 4. Regulation of R-loop stability in the cell: formation of RNA:DNA hybrids can lead to replication and transcription conflicts, DNA damage and double-strand breaks. N6-Methylation of adenosine in the RNA components of R-loops leads to YTHDF2-dependent degradation of RNA:DNA hybrids, thereby reducing the level of genomic instability

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