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Wanted and unwanted modifications of mRNA, and their effect on gene expression and signaling
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DOI：10.1016/j.jbc.2026.113314.png)
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Abstract
En 中文
RNA plays essential roles in transmitting and decoding genetic information, as well as carrying out enzymatic functions during transcription and translation. The function of the polymer is determined by the unique structures of its four nucleobases, which dictate how the molecule interacts with itself, other RNAs, and proteins. As a result, modifications to the bases often impact RNA function by altering these interactions. While we have known for decades that tRNA, rRNA and mRNA are modified, recent research has shed more light on the functional importance of these internal modifications in mRNAs. In addition to enzyme-mediated modifications, mRNA is also susceptible to damage-induced alterations. These arise from endogenous and exogenous alkylating, oxidizing, and cross-linking agents, as well as exposure to UV radiation. Many of these modifications severely disrupt tRNA-mRNA interactions, often leading to ribosome stalling. An integrating theme of this review is that both enzymatic and damage-induced modifications are actively sensed by the cell, with damage-induced modifications in particular engaging dedicated quality control pathways and stress-response programs that regulate gene expression and cellular fate. We begin this review by discussing the most abundant enzymatic mRNA modifications and focus on their impact on translation before turning to damage-induced lesions and the ribosome-based quality control machinery that resolves them. We conclude by discussing the remarkable discovery that damaged mRNA, through its impact on ribosome collisions, activates the integrated stress response (ISR) and ribotoxic stress response (RSR) to reprogram gene expression and, under severe conditions, determine cell fate.
Keywords:
mRNA modification
RNA damage
translation
ribosome
the integrated stress response
ribosome quality control
ribotoxic stress signaling
collided ribosomes
translational control
gene expression
ROS
Reactive Oxygen Species
m6A
N6-methyladenosine
m6Am
N6-2’-O-dimethyladenosine
IRES
Internal Ribosomal Entry Sites
O2•-
Superoxide Anion
•OH
Hydroxyl Radicals
•HO2
Perhydroxyl Radicals
H2O2
Hydrogen Peroxide
ONOO-
Peroxynitrite
8-oxoG
8-oxo-7,8-dihydroguanosine
8-oxoA
8-oxo-7,8-dihydroadenosine
O6-mG
O6-methylguanosine
Tc-NER
Transcription-coupled Nucleotide Excision Repair
NGD
No-Go Decay
RQC
Ribosome Quality Control
ISR
Integrated Stress Response
RSR
Ribotoxic Stress Response
MAPK
Mitogen-Activated Protein Kinase
SAPK
Stress-Activated Protein Kinase
JNK
c-Jun N-terminal Kinase
RACK1
Receptor for Activated Kinase 1
DDR
DNA damage Response
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