Emerging role of RNA acetylation modification ac4C in diseases: Current advances and future challenges

Luo, Jie; Cao, Jingsong; Chen, Cong; Xie, Haiyang

doi:10.1016/j.bcp.2023.115628

Cited by 15 publications

(5 citation statements)

References 126 publications

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“…The most important one is the synthesis of ODNs that contain sensitive epigenetic modifications, such as 4acC (Wang et al., 2022). Such sensitive ODNs are otherwise challenging to obtain while they are needed for projects, e.g., studying mechanisms in epigenetic regulations, isolation of enzymes involved in regulatory processes, studying effects of epigenetic modification on DNA protein interactions, deciphering disease mechanisms, and developing software for detecting epigenetic modifications using Nanopore DNA sequencing (Luo et al., 2023; Seo & Kleiner, 2020; White & Hesselberth, 2022). The protocols can also be used to synthesize ODNs carrying sensitive groups that are not part of the natural epigenetic system, such as alkylated nucleobases and DNA backbone, esters, alkyl halides, and α‐haloamides.…”

Section: Commentarymentioning

confidence: 99%

Oligodeoxynucleotide Synthesis Under Non‐Nucleophilic Deprotection Conditions

Fang,

Chillar,

Yin

et al. 2024

Current Protocols

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This protocol describes a method for the incorporation of sensitive functional groups into oligodeoxynucleotides (ODNs). The nucleophile‐sensitive epigenetic N4‐acetyldeoxycytosine (4acC) DNA modification is used as an example, but other sensitive groups can also be incorporated, e.g., alkyl halide, α‐haloamide, alkyl ester, aryl ester, thioester, and chloropurine groups, all of which are unstable under the basic and nucleophilic deprotection and cleavage conditions used in standard ODN synthesis methods. The method uses a 1,3‐dithian‐2‐yl‐methoxycarbonyl (Dmoc) group that carries a methyl group at the carbon of the methoxy moiety (meDmoc) for the protection of exo‐amines of nucleobases. The growing ODN is anchored to a solid support via a Dmoc linker. With these protecting and linking strategies, ODN deprotection and cleavage are achieved without using any strong bases and nucleophiles. Instead, they can be carried out under nearly neutral non‐nucleophilic oxidative conditions. To increase the length of ODNs that can be synthesized using the meDmoc method, the protocol also describes the synthesis of a PEGylated Dmoc (pDmoc) phosphoramidite. With some of the nucleotides being incorporated with pDmoc‐CE phosphoramidite, the growing ODN on the solid support carries PEG moieties and becomes more soluble, thus enabling longer ODN synthesis. The ODN synthesis method described in this protocol is expected to make many sensitive ODNs that are difficult to synthesize accessible to researchers in multiple areas, such as epigenetics, nanopore sequencing, nucleic acid‐protein interactions, antisense drug development, DNA alkylation carcinogenesis, and DNA nanotechnology. © 2024 Wiley Periodicals LLC.Basic Protocol: Sensitive ODN synthesisSupport Protocol 1: Synthesis of meDmoc‐CE phosphoramiditesSupport Protocol 2: Synthesis of a pDmoc‐CE phosphoramidite

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Section: Commentarymentioning

confidence: 99%

Oligodeoxynucleotide Synthesis Under Non‐Nucleophilic Deprotection Conditions

Fang,

Chillar,

Yin

et al. 2024

Current Protocols

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“…Although there is limited research on ac 4 C, this newly discovered, unique acetylation modification in eukaryotes has a vital role in bioprocesses and immune response. Initially discovered and demonstrated to regulate ribosome maturation and protein translation ability in tRNA and rRNA, ac 4 C was later found to be distributed in mRNA and enriched in the coding sequence (CDS) region using antibodybased sequencing methods (242). On mRNA, ac 4 C in the CDS region can maintain stability and promote translation, while the 5' UTR has been found to potentially inhibit translation initiation by affecting the interaction between mRNA and tRNA/ribosomes (243,244).…”

Section: Regulatory Role Of Ac 4 C and Other Rna Modifications In Ant...mentioning

confidence: 99%

“…On mRNA, ac 4 C in the CDS region can maintain stability and promote translation, while the 5' UTR has been found to potentially inhibit translation initiation by affecting the interaction between mRNA and tRNA/ribosomes (243,244). ac 4 C has been found to be associated with diseases such as cancer, neurodegenerative disorders, and inflammation (242). In viral infections, the presence of ac 4 C on various viral RNAs plays a regulatory role.…”

Section: Regulatory Role Of Ac 4 C and Other Rna Modifications In Ant...mentioning

confidence: 99%

The regulation of antiviral innate immunity through non-m6A RNA modifications

Shen,

Zhang

2023

Front. Immunol.

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The post-transcriptional RNA modifications impact the dynamic regulation of gene expression in diverse biological and physiological processes. Host RNA modifications play an indispensable role in regulating innate immune responses against virus infection in mammals. Meanwhile, the viral RNAs can be deposited with RNA modifications to interfere with the host immune responses. The N6-methyladenosine (m6A) has boosted the recent emergence of RNA epigenetics, due to its high abundance and a transcriptome-wide widespread distribution in mammalian cells, proven to impact antiviral innate immunity. However, the other types of RNA modifications are also involved in regulating antiviral responses, and the functional roles of these non-m6A RNA modifications have not been comprehensively summarized. In this Review, we conclude the regulatory roles of 2’-O-methylation (Nm), 5-methylcytidine (m5C), adenosine-inosine editing (A-to-I editing), pseudouridine (Ψ), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N6,2’-O-dimethyladenosine (m6Am), and N4-acetylcytidine (ac4C) in antiviral innate immunity. We provide a systematic introduction to the biogenesis and functions of these non-m6A RNA modifications in viral RNA, host RNA, and during virus-host interactions, emphasizing the biological functions of RNA modification regulators in antiviral responses. Furthermore, we discussed the recent research progress in the development of antiviral drugs through non-m6A RNA modifications. Collectively, this Review conveys knowledge and inspiration to researchers in multiple disciplines, highlighting the challenges and future directions in RNA epitranscriptome, immunology, and virology.

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“…Functionally, ac4C has been identified in various mRNAs associated with critical cellular processes, including cell proliferation, development, the response to DNA damage, and overall cellular homeostasis ( Arango et al 2018 ; Jiang et al 2023 ; Liu et al 2023a ; Svobodová Kovaříková et al 2023 ). Its deregulation in mRNA is linked to several diseases, notably cancer, and autoimmune disorders, a topic extensively reviewed in recent literature ( Luo et al 2023 ; Zhang et al 2024 ). However, a recent study using a sensitive, base-resolved technique was unable to detect ac4C in mRNA from HeLa and HEK293 cell lines ( Sas-Chen et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

ac4C: a fragile modification with stabilizing functions in RNA metabolism

Schiffers,

Oberdoerffer

2024

RNA

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In recent years, concerted efforts to map and understand epitranscriptomic modifications in mRNA have unveiled new complexities in the regulation of gene expression. These studies cumulatively point to diverse functions in mRNA metabolism, spanning pre-mRNA processing, mRNA degradation, and translation. However, this emerging landscape is not without its intricacies and sources of discrepancies. Disparities in detection methodologies, divergent interpretations of functional outcomes, and the complex nature of biological systems across different cell types pose significant challenges. With a focus of N4-acetylcytidine (ac4C), this review endeavors to unravel conflicting narratives by examining the technological, biological, and methodological factors that have contributed to discrepancies and thwarted research progress. Our goal is to mitigate detection inconsistencies and establish a unified model to elucidate the contribution of ac4C to mRNA metabolism and cellular equilibrium.

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Emerging role of RNA acetylation modification ac4C in diseases: Current advances and future challenges

Cited by 15 publications

References 126 publications

Oligodeoxynucleotide Synthesis Under Non‐Nucleophilic Deprotection Conditions

Oligodeoxynucleotide Synthesis Under Non‐Nucleophilic Deprotection Conditions

The regulation of antiviral innate immunity through non-m6A RNA modifications

ac4C: a fragile modification with stabilizing functions in RNA metabolism

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