CoChat
Sign Up
Cited by 862RNA modifications and cancerRNA and protein synthesis mechanismsRNA regulation and disease

Acetylation of Cytidine in mRNA Promotes Translation Efficiency

Open access
Arango, Daniel, Sturgill, David, Alhusaini, Najwa, Dillman, Allissa A., Sweet, Thomas J., Hanson, Gavin, Hosogane, Masaki, Sinclair, Wilson R. +8 more·2018·Cell
DOI 10.1016/j.cell.2018.10.030PMC PMC6295233
Open this paper in CoChat — free accountOpen PDF

Abstract

Generation of the "epitranscriptome" through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation. Analysis of mRNA half-lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.cell.2018.10.030

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • NAT10 can regulate mRNA translation efficiency by catalyzing the addition of ac4C to the N4 position on thymidines.

    “It can regulate mRNA translation efficiency by catalyzing the addition of ac4C to the N4 position on thymidines.”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [368]

    The Discussion identifies ac4C as N4-acetylcytidine, not a modification of thymidine. It supports the claim that NAT10-catalyzed ac4C regulates mRNA translation, but contradicts the stated nucleotide. (LLM, conf=0.92)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 36

  1. Agris PF, Vendeix FA, and Graham WD (2007). tRNA’s wobble decoding of the genome: 40 years of modification. J Mol Biol 366, 1– 13. 17187822
  2. Anders S, Pyl PT, and Huber W (2015). HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166– 169. 25260700 PMC4287950
  3. Bailey TL, and Elkan C (1994). Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc Int Conf Intell Syst Mol Biol 2, 28– 36. 7584402
  4. Basanta-Sanchez M, Temple S, Ansari SA, D’Amico A, and Agris PF (2016). Attomole quantification and global profile of RNA modifications: Epitranscriptome of human neural stem cells. Nucleic Acids Res 44, e26. 26438536 PMC4756851
  5. Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, de Crecy-Lagard V, Ross R, Limbach PA, Kotter A, (2018). MODOMICS: a database of RNA modification pathways. Nucleic Acids Res 46, D303– D307. 29106616 PMC5753262
  6. Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM, Strein C, Davey NE, Humphreys DT, Preiss T, Steinmetz LM, (2012). Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393– 1406. 22658674
  7. Chimnaronk S, Suzuki T, Manita T, Ikeuchi Y, Yao M, Suzuki T, and Tanaka I (2009). RNA helicase module in an acetyltransferase that modifies a specific tRNA anticodon. EMBO J 28, 1362– 1373. 19322199 PMC2683049
  8. Delatte B, Wang F, Ngoc LV, Collignon E, Bonvin E, Deplus R, Calonne E, Hassabi B, Putmans P, Awe S, (2016). Transcriptome-wide distribution and function of RNA hydroxymethylcytosine. Science 351, 282– 285. 26816380
  9. Dong C, Niu L, Song W, Xiong X, Zhang X, Zhang Z, Yang Y, Yi F, Zhan J, Zhang H, (2016). tRNA modification profiles of the fast-proliferating cancer cells. Biochem Biophys Res Commun 476, 340– 345. 27246735
  10. Hauenschild R, Tserovski L, Schmid K, Thuring K, Winz ML, Sharma S, Entian KD, Wacheul L, Lafontaine DL, Anderson J, (2015). The reverse transcription signature of N-1-methyladenosine in RNA-Seq is sequence dependent. Nucleic Acids Res 43, 9950– 9964. 26365242 PMC4787781
  11. Ingolia NT (2010). Genome-wide translational profiling by ribosome footprinting. Methods Enzymol 470, 119– 142. 20946809
  12. Ito S, Horikawa S, Suzuki T, Kawauchi H, Tanaka Y, Suzuki T, and Suzuki T (2014). Human NAT10 is an ATP-dependent RNA acetyltransferase responsible for N4-acetylcytidine formation in 18S ribosomal RNA. J Biol Chem 289, 35724– 35730. 25411247 PMC4276842
  13. Khatter H, Myasnikov AG, Natchiar SK, and Klaholz BP (2015). Structure of the human 80S ribosome. Nature 520, 640– 645. 25901680
  14. Kim D, Langmead B, and Salzberg SL (2015). HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12, 357– 360. 25751142 PMC4655817
  15. Kumbhar BV, Kamble AD, and Sonawane KD (2013). Conformational preferences of modified nucleoside N4-acetylcytidine, ac4C occur at “wobble” 34th position in the anticodon loop of tRNA. Cell Biochem Biophys 66, 797– 816. 23408308
  16. Langmead B, and Salzberg SL (2012). Fast gapped-read alignment with Bowtie 2. Nat Methods 9, 357– 359. 22388286 PMC3322381
  17. Liu X, Tan Y, Zhang C, Zhang Y, Zhang L, Ren P, Deng H, Luo J, Ke Y, and Du X (2016). NAT10 regulates p53 activation through acetylating p53 at K120 and ubiquitinating Mdm2. EMBO Rep 17, 349– 366. 26882543 PMC4772976
  18. Lv J, Liu H, Wang Q, Tang Z, Hou L, and Zhang B (2003). Molecular cloning of a novel human gene encoding histone acetyltransferase-like protein involved in transcriptional activation of hTERT. Biochem Biophys Res Commun 311, 506– 513. 14592445
  19. Parthasarathy R, Ginell SL, De NC, and Chheda GB (1978). Conformation of N4-acetylcytidine, a modified nucleoside of tRNA, and stereochemistry of codon-anticodon interaction. Biochem Biophys Res Commun 83, 657– 663. 697848
  20. Quinlan AR (2014). BEDTools: The Swiss-Army Tool for Genome Feature Analysis. Current Protocols in Bioinformatics 47, 11.12.11– 34. PMC4213956 25199790
  21. Ramírez F, Dündar F, Diehl S, Grüning BA, and Manke T (2014). deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Research 42, W187– 191. 24799436 PMC4086134
  22. Roundtree IA, Evans ME, Pan T, and He C (2017). Dynamic RNA Modifications in Gene Expression Regulation. Cell 169, 1187– 1200. 28622506 PMC5657247
  23. Sharma S, Langhendries JL, Watzinger P, Kotter P, Entian KD, and Lafontaine DL (2015). Yeast Kre33 and human NAT10 are conserved 18S rRNA cytosine acetyltransferases that modify tRNAs assisted by the adaptor Tan1/THUMPD1. Nucleic Acids Res 43, 2242– 2258. 25653167 PMC4344512
  24. Shen Q, Zheng X, McNutt MA, Guang L, Sun Y, Wang J, Gong Y, Hou L, and Zhang B (2009). NAT10, a nucleolar protein, localizes to the midbody and regulates cytokinesis and acetylation of microtubules. Exp Cell Res 315, 1653– 1667. 19303003
  25. Shen S, Park JW, Lu ZX, Lin L, Henry MD, Wu YN, Zhou Q, and Xing Y (2014). rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc Natl Acad Sci U S A 111, E5593– 5601. 25480548 PMC4280593
  26. Sinclair WR, Arango D, Shrimp JH, Zengeya TT, Thomas JM, Montgomery DC, Fox SD, Andresson T, Oberdoerffer S, and Meier JL (2017). Profiling Cytidine Acetylation with Specific Affinity and Reactivity. ACS Chem Biol 12, 2922– 2926. 29039931 PMC7900898
  27. Squires JE, Patel HR, Nousch M, Sibbritt T, Humphreys DT, Parker BJ, Suter CM, and Preiss T (2012). Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res 40, 5023– 5033. 22344696 PMC3367185
  28. Stern L, and Schulman LH (1978). The role of the minor base N4-acetylcytidine in the function of the Escherichia coli noninitiator methionine transfer RNA. J Biol Chem 253, 6132– 6139. 355249
  29. Sturgill D, Malone JH, Sun X, Smith HE, Rabinow L, Samson ML, and Oliver B (2013). Design of RNA splicing analysis null models for post hoc filtering of Drosophila head RNA-Seq data with the splicing analysis kit (Spanki). BMC bioinformatics 14, 320. 24209455 PMC3827500
  30. Tafforeau L, Zorbas C, Langhendries JL, Mullineux ST, Stamatopoulou V, Mullier R, Wacheul L, and Lafontaine DL (2013). The complexity of human ribosome biogenesis revealed by systematic nucleolar screening of Pre-rRNA processing factors. Mol Cell 51, 539– 551. 23973377
  31. Tani H, Mizutani R, Salam KA, Tano K, Ijiri K, Wakamatsu A, Isogai T, Suzuki Y, and Akimitsu N (2012). Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals. Genome Res 22, 947– 956. 22369889 PMC3337439
  32. Taniguchi T, Miyauchi K, Sakaguchi Y, Yamashita S, Soma A, Tomita K, and Suzuki T (2018). Acetate-dependent tRNA acetylation required for decoding fidelity in protein synthesis. Nat Chem Biol. 30150682
  33. Taoka M, Nobe Y, Yamaki Y, Sato K, Ishikawa H, Izumikawa K, Yamauchi Y, Hirota K, Nakayama H, Takahashi N, (2018). Landscape of the complete RNA chemical modifications in the human 80S ribosome. Nucleic Acids Res. PMC6182160 30202881
  34. Trapnell C, Pachter L, and Salzberg SL (2009). TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105– 1111. 19289445 PMC2672628
  35. Yang X, Yang Y, Sun BF, Chen YS, Xu JW, Lai WY, Li A, Wang X, Bhattarai DP, Xiao W, (2017). 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m5C reader. Cell Res 27, 606– 625. 28418038 PMC5594206
  36. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W, (2008). Model-based analysis of ChIP-Seq (MACS). Genome biology 9, R137. 18798982 PMC2592715

Cited by

Sorted by citations

Authors
Arango, D., Sturgill, D., Alhusaini, N., Dillman, A. A., Sweet, T. J., Hanson, G., Hosogane, M., Sinclair, W. R., Nanan, K. K., Mandler, M. D., Fox, S. D., Zengeya, T. T., Andresson, T., Meier, J. L., Coller, J., & Oberdoerffer, S.
Affiliations
  • National Institutes of Health (US)
  • Case Western Reserve University (US)
  • Frederick National Laboratory for Cancer Research (US)
Corresponding author
Oberdoerffer, Shalini
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2018-12
Volume
175
Issue
7
Pages
1872-1886.e24
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2018.10.030
PMC
PMC6295233
OpenAlex
W2901932654
Cited by
862
References
4
Citations by year
2026: 125 · 2025: 172 · 2024: 157 · 2023: 124 · 2022: 93 · 2021: 71 · 2020: 68 · 2019: 48 · 2018: 3
FWCI
17.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Intramural Research Program of the National Institutes of Health
  • NCI
  • Center for Cancer Research
  • NIH (GM118018, GM125086)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
N4-acetylcytidine, mRNA acetylation, NAT10, epitranscriptome, post-transcriptional RNA modification, translation efficiency, mRNA stability, mRNA half-life
MeSH terms
Acetylation, Cytidine, HeLa Cells, Humans, RNA, Messenger, Protein Biosynthesis, N-Terminal Acetyltransferases, N-Terminal Acetyltransferase E

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review