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.

Keywords: cellular functions; epitranscriptomics; m1A; m5C; m6A; therapeutics.

FIGURE 1

Schematic highlighting m⁶A writers, erasers, and readers on mRNA. m⁶A patterning on mRNA is mediated by the actions of writers (METTL3, METTL14, WTAP, VIRMA/KIAA1429, RBM15/15B, ZC3H13), erasers (ALKBH5, FTO), and reader enzymes (YTHDF1-3, YTHDC1/2, IGF2BP1-3, HNRNPA2B1, and eIF3).

FIGURE 2

Representative schematic highlighting the role of METTL3 in apoptosis. (A) METTL3 prohibits the expression of both pro-apoptotic genes and proteins (red) as well as promotes the expression of anti-apoptotic genes and pathways (green), leading to overall decreased apoptosis. (B) Without METTL3 expression, pro-apoptotic genes and proteins are expressed (green), while anti-apoptotic pathways are inhibited, leading to the induction of apoptosis.

FIGURE 3

The m⁶A-dependent roles of FTO in adipocyte and lipid metabolism. FTO regulates and promotes adipogenesis and lipogenesis by demethylating mRNA transcripts of genes involved in adipogenesis (Ccna2, Cdk2, Runx1t1) and lipogenesis (Srebp1c).

FIGURE 4

Review of the role of m⁶A within the DNA Damage Response. The role of m⁶A with the DNA Damage Response is dependent on the DNA damaging agent, highlighted through the distinct mechanisms that are employed upon exposure to UVA/UVC (A), UVB (B), X-ray/Zeocin (C), or Stress (D).

FIGURE 5

Overview of m⁶A in cellular processes. In this review, we highlight the role of RNA modifications in cellular processes such as cell death, proliferation, senescence, differentiation, migration, metabolism, autophagy, the DNA damage response, and LLPS. Within these processes, RNA modifications assume unique and context-dependent functions.

FIGURE 6

Overview of m⁵C in cellular processes. In this review, we highlight the role of RNA modifications in cellular processes such as cell death, proliferation, senescence, differentiation, migration, metabolism, and the DNA damage response. Within these processes, RNA modifications assume unique and context-dependent functions.

FIGURE 7

Overview of m¹A in cellular processes. In this review, we highlight the role of RNA modifications in cellular processes such as cell death, proliferation, senescence, migration, metabolism, the DNA damage response, and LLPS. Within these processes, RNA modifications assume unique and context-dependent functions.