N6-methyladenosine modifications: interactions with novel RNA-binding proteins and roles in signal transduction

Abstract

RNA epigenetics has received a great deal of attention in recent years, and the reversible N6-methyladenosine (m6A) modification on messenger RNAs (mRNAs) has emerged as a widespread phenomenon. The vital roles of m6A in diverse biological processes are dependent on many RNA-binding proteins (RBPs) with 'reader' or 'nonreader' functions. Moreover, m6A effector proteins affect cellular processes, such as stem cell differentiation, tumor development and the immune response by controlling signal transduction. This review provides an overview of the interactions of m6A with various RBPs, including the 'reader' proteins (excluding the YT521-B homology (YTH) domain proteins and the heterogeneous nuclear ribonucleoproteins (hnRNPs)), and the functional 'nonreader' proteins, and this review focuses on their specific RNA-binding domains and their associations with other m6A effectors. Furthermore, we summarize key m6A-marked targets in distinct signaling pathways, leading to a better understanding of the cellular m6A machinery.

Keywords: M6a reader; RNA-binding protein; protein domain; signaling pathway.

Figure 1.

A proposed model of RBPs in the m6A field. (a) Cap-independent translation is mediated by m6A and requires the eIF3 (reader protein), ABCF1, and Mettl3 proteins that bind to internal m6A residues but not to the m7G cap [33,34]. (b) PCIF1 interacts with RNAPII and regulates the N6-methylation of m6Am, which promotes the translation of capped mRNAs [36]. (c) Ythdf1 or Mettl3 promotes translation with the help of eIF3 and mRNA circularization [37,38]. (d) IGF2BPs promote the translation of m6A-mRNAs either by stabilizing targets, such as MYC with the aid of mRNA stabilizers, including HuR, MATR3 and PABPC1 or by antagonizing miRNA-directed mRNA repression [39,45]. (e) Prrc2a stabilizes olig2 mRNA by binding to m6A sites in the CDS and competes with Ythdf2 to regulate RNA stability [46]. (f) FMR1 stabilizes m6A mRNAs by interacting with Ythdf2 or inhibits translation by competing with Ythdf1 [48,49]. (g) HuR stabilizes IGFBP3 mRNA by preventing miRNA targeting [53]. (h) HuR promotes the stability of the demethylated mRNA of FOXM1, which is mediated by Alkbh5, and the cooperation between Alkbh5 and FOXM1-AS.^[105] (i) Mettl3 stabilizes the mRNA of SOX2 by recruiting HuR [57]. (j) Slow or paused RNAPII dynamics facilitate MTC binding and m6A deposition, leading to reduced translation efficiency [59]. (k) Ythdc2 stabilizes m6A-mRNAs by interacting with XRN1 [60]. (l) Alkbh5 inhibits the nuclear export of several antiviral transcripts by recruiting DDX46 [62]. (m) Mettl3, recruited by PARP, promotes m6A deposition and subsequent Pol κ binding accompanied by Mettl14, leading to cell survival from DDR [9]. (n) Mettl3 interacts with RdRp-3D and regulates the sumoylation and ubiquitination of RdRp-3D that can promote viral replication [63]. (o) The loss of FTO promotes m6A deposition and the SRSF2 binding ability, leading to the increased inclusion of target exons [69]. (p) Ythdc1 recruits SRSF3 and SRSF7 to promote exon inclusion; Ythdc1 recruits SRSF3 and NXF1 to promote nuclear export [7,70]. (q) CEBPZ recruits Mettl3 to gene promoter regions to augment their translation [73]. (r) TREX interacts with Ythdc1 to promote nuclear export [74].

Figure 2.

Effects of m6A on the AKT signaling pathway.

Figure 3.

Effects of m6A on the JAK/STAT signaling pathway.