# The Emerging Roles of RNA Modifications in Glioblastoma
## 2 RNA Modifications  
RNA modifications refer to dynamic, reversible covalent alterations present in the oligonucleotides of RNAs, including mRNAs, tRNAs, rRNAs and spliceosomal RNAs (sRNAs). These changes are commonly present in the transcriptome. Since 1957, when pseudouridine (\(\Downarrow\), also known as the fifth RNA nucleotide) was discovered by [PERSON] and [PERSON] [26], at least 170 kinds of RNA modifications have been identified [26]. Actually, m\({}^{7}\)G (7-methylguanosine, also known as 5\({}^{\prime}\) cap) and 3\({}^{\prime}\) poly(A) tail are well-known modifications in mRNA [27]. In 2012, the NGS method was developed, and since then, many widespread and conserved internal RNA modifications in RNAs were identified [22]. In eukaryotic RNA, the most commonly found modifications are N\({}^{6}\)-methyladenosine (m\({}^{6}\)A), N\({}^{6}\), 2\({}^{\prime}\)O-dimethyladenosine (m\({}^{6}\)A), 5-methylcytosine (m\({}^{5}\)C), 5-hydroxymethylcytosine (hm\({}^{5}\)C), N\({}^{1}\)-methyladenosine (m\({}^{1}\)A), inosine (I), N\({}^{4}\)-acetylcytidine (ac4C), \(\Downarrow\), uridylation (U-tail), 2-methylthio-N\({}^{6}\)-(_cis_- hydroxyisopentenyl)adenosine (ms\({}^{2}\)\({}^{6}\)A), 3-methylcytosine (m\({}^{3}\)C), m\({}^{7}\)G, 7-methylguanosine cap (m\({}^{7}\)Gpp(pN)), queuosine (Q), wybutosine and derivatives (yW), 5-methyluridine (m\({}^{5}\)U), 5-carbamoylmethyluridine (ncm\({}^{5}\)U), 5-methoxycarbonylmethyl-2-thiouridine (mcm\({}^{5}\)S\({}^{2}\)U), dihydrouridine (D), 2\({}^{\prime}\)-O-methylucleotide (Nm), N\({}^{6}\)-isopentenyladenosine (f\({}^{6}\)A), and 5\({}^{\prime}\)-phosphate monomethylation (m(pN)) [28; 29; 30]. Most of these modifications have been found in mRNAs. Moreover, eukaryotic tRNAs also contain many modifications (13 modifications per molecule on average) to maintain their chemical diversity, thereby contributing to decoding fidelity, folding efficiency, cellular stability and localization [31]. rRNAs also contain abundant modifications (>200 sites per molecule) including 2\({}^{\prime}\)-O-methyls, pseudouridines, and base methylations in the peptidyl transferase center, the A, P and E sites of tRNA- and mRNA binding [32], thereby maintaining their functions. In addition, sRNAs also contain moderate amountsof modifications (>50 sites per molecule), some of which play important roles in the RNA splicing actions [33]. Each modification has its writers, the enzymes that deposit RNA chemical marks; erasers, the enzymes that remove these marks; and readers, the proteins that selectively recognize and bind to these marks (Figure 1). Collectively, the writers, erasers and readers also refer to as RNA-modifying proteins (RMPs). These modifications are not only needed for normal function but also play essential roles in pathological processes, such as tumorigenesis. Figure 1: Functions of m6A modification and its writers, erasers and readers in GBM. Abbreviations: RNA-modifying proteins (RMPs): ALKBH5, \(\alpha\)-Ketoglutarate-dependent dioxygenase alkB homolog 5; eIF3a/b/h, eukaryotic translation initiation factor 3a/b/h; FTO, Fat mass and obesity-associated protein; Hakai, Cbl proto-oncogene like 1, CBLL1; hnRNFA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; hnRNFC, heterogeneous nuclear ribonucleoprotein C1/C2; IGF2 BP1/2/3, insulin-like growth factor 2 mRNA-binding protein 1/2/3; METTLE3/14, methyltransferase like 3/14; RBM15/15B, RNA-binding motif protein 15/15B; VIRMA, Virilizer like m6A methyltransferase associated protein; WTAP, Wilms’ tumor 1-associated protein; YTHDF1/2/3, YTH N6-methyladenosine RNA binding protein 1/2/3; YTHDC1/2/3, YTH domain-containing 1/2/3; ZC3H13, zinc finger CCCH domain-containing protein 13.