Emerging roles of RNA ac4C modification and NAT10 in mammalian development and human diseases

Available online 7 December 2023, 108576

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RNA ac4C modification is a novel and rare chemical modification observed in mRNA. Traditional biochemical studies had primarily associated ac4C modification with tRNA and rRNA until in 2018, Arango D et al. first reported the presence of ac4C modification on mRNA and demonstrated its critical role in mRNA stability and translation regulation. Furthermore, they established that the ac4C modification on mRNA is mediated by the classical N-acetyltransferase NAT10. Subsequent studies have underscored the essential implications of NAT10 and mRNA ac4C modification across both physiological and pathological regulatory processes. In this review, we aimed to explore the discovery history of RNA ac4C modification, its detection methods, and its regulatory mechanisms in disease and physiological development. We offer a forward-looking examination and discourse concerning the employment of RNA ac4C modification as a prospective therapeutic strategy across diverse diseases. Furthermore, we comprehensively summarize the functions and mechanisms of NAT10 in gene expression regulation and pathogenesis independent of RNA ac4C modification.

Section snippetsIntroduction: Dynamic regulation of mRNA modifications and their crucial roles in gene expression regulation

Within the realm of genetic information transfer, it is well established that post-transcriptional regulation, orchestrated by the RNA-protein machinery and non-coding RNAs, assumes a pivotal role. This regulatory apparatus is widely acknowledged to be involved in disease progression (Slack & Chinnaiyan, 2019; Gerstberger, Hafner, & Tuschl, 2014; Gebauer, Schwarzl, Valcárcel, et al., 2021). With recent advancements in biochemistry and molecular biology, scientists have discovered complex and

mRNA ac4C modification mechanisms in disease and physiological development

Since the discovery of ac4C modification on mRNA and its key biological regulatory functions by Arango et al. (Arango et al., 2018), medical scientists have been extensively examining the role of NAT10-mediated mRNA ac4C modification in disease progression across various disease models. Employing high-throughput sequencing technologies such as RIP-, CLIP-, and acRIP-seq, the specific mechanisms and downstream targets of NAT10 in disease and physiological regulation have been elucidated. Here,

Non-mRNA ac4C-dependent regulatory mechanisms and functions of NAT10

In addition to the classical pathway of regulating RNA stability and translation through mRNA ac4C modification, NAT10 plays major roles in protein modification (Zheng, Tan, Liu, et al., 2022b), rRNA biosynthesis (Cai, Liu, Zhang, et al., 2017; Liu, Cai, Zhang, et al., 2018), and other non-mRNA ac4C-dependent non-canonical regulatory pathways. NAT10 relies on these non-canonical regulatory pathways to exert its functions in physiological and pathological processes. Here, we summarize the

Identification methods and discovery process of RNA ac4C modification

With the development of advanced biochemistry, molecular biology, and genomic sequencing, methods for identifying and detecting RNA ac4C modification have rapidly evolved. In terms of the comprehensive detection of ac4C modification, Soll D’s team first discovered the presence of this modification in yeast tRNA transcripts using post-labeling fingerprinting and rapid gel sequencing techniques (Rafalski, Kohli, Agris, et al., 1979). However, the regulatory function and mechanism of this rare

Prospects of targeting NAT10 and ac4C modification in disease diagnosis and treatment

Given the critical roles of NAT10 and RNA ac4C modification in disease progression, numerous studies have attempted to use NAT10 small molecule inhibitors for therapeutic interventions. In 2014, Remodelin was first identified as a small molecule inhibitor of NAT10 using computational biology methods. The research demonstrated the therapeutic effects of NAT10 inhibition through chemical means in diseases such as HGPS and progeria (Larrieu et al., 2014). Subsequent investigations explored

Conclusion

In this review, we summarized the majority of research on RNA ac4C and NAT10, analyzing their pivotal biological functions, research methodologies, clinical translational potential, and relevance across multidisciplinary perspectives, encompassing biochemistry, molecular biology, medicine, and pharmacy. This comprehensive analysis offers a new perspective for scientists engaged in the domain of RNA modifications. In practical application, NAT10 and RNA ac4C modification present themselves as

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Funding

This study was supported by Research Start-up Funding for Taihe Hospital Affiliated to Hubei Medical University, Hubei Province’s Outstanding Medical Academic Leader Program, Advantage Discipline Group (Public Health) Project in Higher Education of Hubei Province (2021-2025) (2023PHXKQ1), the Foundation of Health Commission of Hubei Province (WJ2021F037, WJ2021M051), and Project of Hubei University of Medicine (FDFR201902, 2020XGFYZR05, YC2023047, YC2021033, and YC2022035), Special Fund for

Authors' contributions

Yigan Zhang, Zhongji Meng, Chen Juan, Yanbin Dong, wrote this manuscript; Yumei Lei, Shuwen Chen, Fange Zhou drew the figures and tables in the manuscript; Lv Wei, Siyuan Sun, Zhiwen Zhao,Bonan Chen proofread and supervised the manuscript writing process; All authors reviewed the manuscript. Yigan Zhang, Yumei Lei,Yanbin Dong contributed equally to the work.

CRediT authorship contribution statement

Yigan Zhang: Writing – review & editing, Writing – original draft, Funding acquisition, Conceptualization. Yumei Lei: Writing – review & editing, Writing – original draft, Visualization. Yanbin Dong: Writing – review & editing, Conceptualization. Shuwen Chen: Writing – review & editing, Visualization. Siyuan Sun: Writing – review & editing, Writing – original draft. Fange Zhou: Writing – review & editing. Zhiwen Zhao: Writing – review & editing. Bonan Chen: Writing – review & editing,

Declaration of Competing Interest

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

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