Roles of RNA Modifications in Diverse Cellular Functions

Abstract

Chemical modifications of RNA molecules regulate both RNA metabolism and fate. The deposition and function of these modifications are mediated by the actions of writer, reader, and eraser proteins. At the cellular level, RNA modifications regulate several cellular processes including cell death, proliferation, senescence, differentiation, migration, metabolism, autophagy, the DNA damage response, and liquid-liquid phase separation. Emerging evidence demonstrates that RNA modifications play active roles in the physiology and etiology of multiple diseases due to their pervasive roles in cellular functions. Here, we will summarize recent advances in the regulatory and functional role of RNA modifications in these cellular functions, emphasizing the context-specific roles of RNA modifications in mammalian systems. As m6A is the best studied RNA modification in biological processes, this review will summarize the emerging advances on the diverse roles of m6A in cellular functions. In addition, we will also provide an overview for the cellular functions of other RNA modifications, including m5C and m1A. Furthermore, we will also discuss the roles of RNA modifications within the context of disease etiologies and highlight recent advances in the development of therapeutics that target RNA modifications. Elucidating these context-specific functions will increase our understanding of how these modifications become dysregulated during disease pathogenesis and may provide new opportunities for improving disease prevention and therapy by targeting these pathways.

The Role of RNA Modification in HIV-1 Infection

“…In the 1970s, researchers discovered the existence of m 5 C in RNA, and high-throughput detection methods found that m 5 C is an RNA modification widely present in mRNA and lncRNA, including transfer RNA (tRNA), ribosomal RNA (rRNA), Long non-coding RNA (lncRNA), small nuclear RNA (snRNA), microRNA (miRNA), and enhancer RNA (eRNA) [94]. Modifications at specific positions of m 5 C in mRNA show different regulatory activities, they can promote or inhibit translation; in tRNA, m 5 C can stabilize secondary structure and affect anticodon stem-loop conformation; in rRNA, m 5 C can affect translation preservation Authenticity [52]. The m 5 C methyltransferase usually uses S-adenosylmethionine (SAM) as the methyl donor to transfer the methyl group to the fifth carbon position of the RNA cytosine base [95].…”

“…m 5 C promotes viral mRNA translation. In the study of Courtney, a highly prevalent modification of m 5 C was detected on HIV-1 gRNA in infected cells, with m 5 C levels about 14 times higher than cellular mRNA.…”

“…Furthermore, RNA modifications at the cellular level regulate a variety of cellular processes, including cell death, proliferation, aging, differentiation, migration, metabolism, autophagy, DNA damage response, etc. They play an important role in the physiology and etiology of many diseases [ 5 ].…”

“…Although our understanding of the importance of RNA modification in physiological and pathological processes is rapidly increasing, little is known about the function of RNA modification in the mammalian immune system or its role in host-pathogen interactions. In this paper, the m 6 A, m 1 A, m 5 C, m 7 G, m 6 Am, pseudouridine (ψ), 2 -O-methylation (2 -O-Me or Nm) and N4-acetylcytidine (ac 4 C) modifications (Figure 1) as well as their roles in HIV-1 infection are introduced.…”

Interaction between N6-methyladenosine and autophagy in the regulation of bone and tissue degeneration

“…Numerous studies have revealed that m6A methylation plays a crucial role in the regulation of the degeneration process and mediates the occurrence and progression of multiple degeneration-related disorders (Li et al, 2022b;Peng et al, 2022). Intriguingly, prior studies reported that epigenetic modifications including m6A methylation played a prominent role in autophagy regulation (Tang et al, 2022;Wilkinson et al, 2022). Moreover, m6A modification has been reported to directly regulate the expression of autophagy-related (ATG) genes and modulate the cellular autophagy level, and the effects of the m6A methylation on autophagy are dependent on the disease context (Han et al, 2021).…”