NSUN2-Mediated M5C Methylation and METTL3/METTL14-Mediated M6A Methylation Cooperatively Enhance P21 Translation

Overview

Journal J Cell Biochem

Specialties Biochemistry
Cell Biology

Date 2017 Mar 2

PMID 28247949

Citations 138

Authors

Qiu Li

Xiu Li

Hao Tang

Bin Jiang

Yali Dou

Myriam Gorospe

Wengong Wang

Affiliations

Soon will be listed here.

Abstract

N6-methyladenosine (m6A) and m5C methylation are two major types of RNA methylation, but the impact of joint modifications on the same mRNA is unknown. Here, we show that in p21 3'UTR, NSUN2 catalyzes m5C modification and METTL3/METTL14 catalyzes m6A modification. Interestingly, methylation at m6A by METTL3/METTL14 facilitates the methylation of m5C by NSUN2, and vice versa. NSUN2-mediated m5C and METTL3/METTL14-mediated m6A methylation synergistically enhance p21 expression at the translational level, leading to elevated expression of p21 in oxidative stress-induced cellular senescence. Our findings on p21 mRNA methylation and expression reveal that joint m6A and m5C modification of the same RNA may influence each other, coordinately affecting protein expression patterns. J. Cell. Biochem. 118: 2587-2598, 2017. © 2017 Wiley Periodicals, Inc.

Citing Articles

Detection, molecular function and mechanisms of m5C in cancer.

Zhang L, Li Y, Li L, Yao F, Cai M, Ye D Clin Transl Med. 2025; 15(3):e70239.

PMID: 40008496 PMC: 11862898. DOI: 10.1002/ctm2.70239.

Cellular senescence: from homeostasis to pathological implications and therapeutic strategies.

Li C, Yuan Y, Jia Y, Zhou Q, Wang Q, Jiang X Front Immunol. 2025; 16:1534263.

PMID: 39963130 PMC: 11830604. DOI: 10.3389/fimmu.2025.1534263.

Integrative analysis of 5-methylcytosine associated signature in papillary thyroid cancer.

Ding Y, Li X, Wang W, Cai L Sci Rep. 2025; 15(1):4405.

PMID: 39910191 PMC: 11799374. DOI: 10.1038/s41598-025-88657-2.

Deciphering the interplay between SETD2 mediated H3K36me3 and RNA N6-methyladenosine in clear cell renal cell carcinoma (ccRCC).

Shaikh S, Zhao X, Wagner R, Pan X, Hlady R, Wang L Epigenetics. 2025; 20(1):2456418.

PMID: 39874221 PMC: 11776469. DOI: 10.1080/15592294.2025.2456418.

Most m5C Modifications in Mammalian mRNAs are Nonadaptive.

Li Z, Mi K, Xu C Mol Biol Evol. 2025; 42(1.

PMID: 39824217 PMC: 11756383. DOI: 10.1093/molbev/msaf008.

References

Meyer K, Saletore Y, Zumbo P, Elemento O, Mason C, Jaffrey S . Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell. 2012; 149(7):1635-46. PMC: 3383396. DOI: 10.1016/j.cell.2012.05.003. View

Bjork G, Ericson J, Gustafsson C, Hagervall T, Jonsson Y, Wikstrom P . Transfer RNA modification. Annu Rev Biochem. 1987; 56:263-87. DOI: 10.1146/annurev.bi.56.070187.001403. View

Gartel A, Tyner A . Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res. 1999; 246(2):280-9. DOI: 10.1006/excr.1998.4319. View

Li X, Xiong X, Wang K, Wang L, Shu X, Ma S . Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome. Nat Chem Biol. 2016; 12(5):311-6. DOI: 10.1038/nchembio.2040. View

Fu L, Amato N, Wang P, McGowan S, Niedernhofer L, Wang Y . Simultaneous Quantification of Methylated Cytidine and Adenosine in Cellular and Tissue RNA by Nano-Flow Liquid Chromatography-Tandem Mass Spectrometry Coupled with the Stable Isotope-Dilution Method. Anal Chem. 2015; 87(15):7653-9. PMC: 4711271. DOI: 10.1021/acs.analchem.5b00951. View

Gorospe M, Wang X, Guyton K, Holbrook N . Protective role of p21(Waf1/Cip1) against prostaglandin A2-mediated apoptosis of human colorectal carcinoma cells. Mol Cell Biol. 1996; 16(12):6654-60. PMC: 231667. DOI: 10.1128/MCB.16.12.6654. View

DUBIN D, Taylor R . The methylation state of poly A-containing messenger RNA from cultured hamster cells. Nucleic Acids Res. 1975; 2(10):1653-68. PMC: 343535. DOI: 10.1093/nar/2.10.1653. View

Hussain S, Sajini A, Blanco S, Dietmann S, Lombard P, Sugimoto Y . NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs. Cell Rep. 2013; 4(2):255-61. PMC: 3730056. DOI: 10.1016/j.celrep.2013.06.029. View

Gorospe M, Holbrook N . Role of p21 in prostaglandin A2-mediated cellular arrest and death. Cancer Res. 1996; 56(3):475-9. View

10.

Tang H, Fan X, Xing J, Liu Z, Jiang B, Dou Y . NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation. Aging (Albany NY). 2015; 7(12):1143-58. PMC: 4712338. DOI: 10.18632/aging.100860. View

11.

Lin S, Gregory R . Methyltransferases modulate RNA stability in embryonic stem cells. Nat Cell Biol. 2014; 16(2):129-31. DOI: 10.1038/ncb2914. View

12.

Cai X, Hu Y, Tang H, Hu H, Pang L, Xing J . RNA methyltransferase NSUN2 promotes stress-induced HUVEC senescence. Oncotarget. 2016; 7(15):19099-110. PMC: 4991368. DOI: 10.18632/oncotarget.8087. View

13.

Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L . A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2013; 10(2):93-5. PMC: 3911877. DOI: 10.1038/nchembio.1432. View

14.

Timchenko N, Wilde M, Nakanishi M, Smith J, Darlington G . CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes Dev. 1996; 10(7):804-15. DOI: 10.1101/gad.10.7.804. View

15.

Gorospe M, Cirielli C, Wang X, Seth P, Capogrossi M, Holbrook N . p21(Waf1/Cip1) protects against p53-mediated apoptosis of human melanoma cells. Oncogene. 1997; 14(8):929-35. DOI: 10.1038/sj.onc.1200897. View

16.

Zhao B, Roundtree I, He C . Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2016; 18(1):31-42. PMC: 5167638. DOI: 10.1038/nrm.2016.132. View

17.

Wang Y, Li Y, Toth J, Petroski M, Zhang Z, Zhao J . N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol. 2014; 16(2):191-8. PMC: 4640932. DOI: 10.1038/ncb2902. View

18.

Blanco S, Bandiera R, Popis M, Hussain S, Lombard P, Aleksic J . Stem cell function and stress response are controlled by protein synthesis. Nature. 2016; 534(7607):335-40. PMC: 5040503. DOI: 10.1038/nature18282. View

19.

Zhang X, Liu Z, Yi J, Tang H, Xing J, Yu M . The tRNA methyltransferase NSun2 stabilizes p16INK⁴ mRNA by methylating the 3'-untranslated region of p16. Nat Commun. 2012; 3:712. PMC: 3509206. DOI: 10.1038/ncomms1692. View

20.

Carroll S, Narayan P, ROTTMAN F . N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA. Mol Cell Biol. 1990; 10(9):4456-65. PMC: 361031. DOI: 10.1128/mcb.10.9.4456-4465.1990. View