METTL3-mediated M6A Modification Stabilizes TERRA and Maintains Telomere Stability

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2022 Nov 18

PMID 36399511

Authors

Liping Chen

Canfeng Zhang

Wenbin Ma

Junjiu Huang

Yong Zhao

Haiying Liu

Affiliations

Soon will be listed here.

Abstract

Telomeric repeat-containing RNA (TERRA) is a type of long non-coding RNA transcribed from telomeres, and it forms R-loops by invasion into telomeric DNA. Since either an excessive or inadequate number of R-loops leads to telomere instability, the TERRA levels need to be delicately modulated. In this study, we found that m6A modification presents on the subtelomeric regions of TERRA and stabilizes it, and the loss of METTL3 impacts telomere stability. Mechanically, the m6A modification on TERRA is catalyzed by METTL3, recognized and stabilized by the m6A reader YTHDC1. Knockdown of either METTL3 or YTHDC1 enhances TERRA degradation. The m6A-modified TERRA forms R-loops and promotes homologous recombination which is essential for the alternative lengthening of telomeres (ALT) pathway in cancer cells. METTL3 depletion leads to R-loop reduction, telomere shortening and instability. Altogether, these findings reveal that METTL3 protects telomeres by catalyzing m6A modification on TERRA, indicating that inhibition or deletion of METTL3 is potentially a new avenue for ALT cancer therapy.

Citing Articles

Recent Advances in the Mutual Regulation of m6A Modification and Non-Coding RNAs in Atherosclerosis.

Wang Y, Ling S, Feng H, Hua J, Han Z, Chai R Int J Gen Med. 2025; 18:1047-1073.

PMID: 40026815 PMC: 11871936. DOI: 10.2147/IJGM.S508197.

N6-methyladenosine (m6A)-forming enzyme METTL3 controls UAF1 stability to promote inflammation in a model of colitis by stimulating NLRP3.

Lai Y, Liu J, Hu X, Zeng X, Gao P Sci Rep. 2025; 15(1):5876.

PMID: 39966502 PMC: 11836354. DOI: 10.1038/s41598-025-88435-0.

Epigenetic regulation in female reproduction: the impact of m6A on maternal-fetal health.

Li P, Lin Y, Ma H, Zhang J, Zhang Q, Yan R Cell Death Discov. 2025; 11(1):43.

PMID: 39904996 PMC: 11794895. DOI: 10.1038/s41420-025-02324-z.

The role of m6A methylation genes in predicting poor prognosis in sepsis: identifying key biomarkers and therapeutic targets.

Wang S, Shen S, Cheng N, Zhou W, Yu W, Liang D Eur J Med Res. 2024; 29(1):608.

PMID: 39702336 PMC: 11657712. DOI: 10.1186/s40001-024-02194-8.

Cross-regulation of RNA methylation modifications and R-loops: from molecular mechanisms to clinical implications.

Wu Y, Lin S, Chen H, Zheng X Cell Mol Life Sci. 2024; 82(1):1.

PMID: 39656315 PMC: 11631829. DOI: 10.1007/s00018-024-05536-1.

References

Schoeftner S, Blasco M . Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol. 2007; 10(2):228-36. DOI: 10.1038/ncb1685. View

Dominissini D, Moshitch-Moshkovitz S, Salmon-Divon M, Amariglio N, Rechavi G . Transcriptome-wide mapping of N(6)-methyladenosine by m(6)A-seq based on immunocapturing and massively parallel sequencing. Nat Protoc. 2013; 8(1):176-89. DOI: 10.1038/nprot.2012.148. View

Xiao W, Adhikari S, Dahal U, Chen Y, Hao Y, Sun B . Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Mol Cell. 2016; 61(4):507-519. DOI: 10.1016/j.molcel.2016.01.012. View

Cesare A, Reddel R . Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet. 2010; 11(5):319-30. DOI: 10.1038/nrg2763. View

Alarcon C, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie S . HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell. 2015; 162(6):1299-308. PMC: 4673968. DOI: 10.1016/j.cell.2015.08.011. View

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

Vohhodina J, Goehring L, Liu B, Kong Q, Botchkarev Jr V, Huynh M . BRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage. Nat Commun. 2021; 12(1):3542. PMC: 8192922. DOI: 10.1038/s41467-021-23716-6. View

Azzalin C, Reichenbach P, Khoriauli L, Giulotto E, Lingner J . Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science. 2007; 318(5851):798-801. DOI: 10.1126/science.1147182. View

Fernandes R, Feretzaki M, Lingner J . The makings of TERRA R-loops at chromosome ends. Cell Cycle. 2021; 20(18):1745-1759. PMC: 8525998. DOI: 10.1080/15384101.2021.1962638. View

10.

Brill S, Stillman B . Replication factor-A from Saccharomyces cerevisiae is encoded by three essential genes coordinately expressed at S phase. Genes Dev. 1991; 5(9):1589-600. DOI: 10.1101/gad.5.9.1589. View

11.

Zhao Y, Sfeir A, Zou Y, Buseman C, Chow T, Shay J . Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells. Cell. 2009; 138(3):463-75. PMC: 2726829. DOI: 10.1016/j.cell.2009.05.026. View

12.

Cusanelli E, Perez Romero C, Chartrand P . Telomeric noncoding RNA TERRA is induced by telomere shortening to nucleate telomerase molecules at short telomeres. Mol Cell. 2013; 51(6):780-91. DOI: 10.1016/j.molcel.2013.08.029. View

13.

Nie X, Xiao D, Ge Y, Xie Y, Zhou H, Zheng T . TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication. Cell Death Differ. 2020; 28(3):1062-1075. PMC: 7937677. DOI: 10.1038/s41418-020-00637-3. View

14.

Liu H, Xie Y, Zhang Z, Mao P, Liu J, Ma W . Telomeric Recombination Induced by DNA Damage Results in Telomere Extension and Length Heterogeneity. Neoplasia. 2018; 20(9):905-916. PMC: 6097467. DOI: 10.1016/j.neo.2018.07.004. View

15.

Lopez de Silanes I, Grana O, De Bonis M, Dominguez O, Pisano D, Blasco M . Identification of TERRA locus unveils a telomere protection role through association to nearly all chromosomes. Nat Commun. 2014; 5:4723. PMC: 4164772. DOI: 10.1038/ncomms5723. View

16.

Chu H, Cifuentes-Rojas C, Kesner B, Aeby E, Lee H, Wei C . TERRA RNA Antagonizes ATRX and Protects Telomeres. Cell. 2017; 170(1):86-101.e16. PMC: 5552367. DOI: 10.1016/j.cell.2017.06.017. View

17.

Nittis T, Guittat L, Stewart S . Alternative lengthening of telomeres (ALT) and chromatin: is there a connection?. Biochimie. 2007; 90(1):5-12. DOI: 10.1016/j.biochi.2007.08.009. View

18.

Liu S, Li Q, Chen K, Zhang Q, Li G, Zhuo L . The emerging molecular mechanism of mA modulators in tumorigenesis and cancer progression. Biomed Pharmacother. 2020; 127:110098. DOI: 10.1016/j.biopha.2020.110098. View

19.

Sugiyama T, Kowalczykowski S . Rad52 protein associates with replication protein A (RPA)-single-stranded DNA to accelerate Rad51-mediated displacement of RPA and presynaptic complex formation. J Biol Chem. 2002; 277(35):31663-72. DOI: 10.1074/jbc.M203494200. View

20.

Stauffer M, Chazin W . Physical interaction between replication protein A and Rad51 promotes exchange on single-stranded DNA. J Biol Chem. 2004; 279(24):25638-45. DOI: 10.1074/jbc.M400029200. View