Skip to main content
SpringerLink
Log in

The Functions of N6-Methyladenosine in Nuclear RNAs

  • REVIEW
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

N6-methyladenosine (m6A) is one of the most common modifications in both eukaryotic and prokaryotic mRNAs. It has been experimentally confirmed that m6A methylation is involved in the regulation of stability and translation of various mRNAs. Until recently, the majority of m6A-related studies have been focused on the cytoplasmic functions of this modification. Here, we review new data on the role of m6A in several key biological processes taking place in the cell nucleus, such as transcription, chromatin organization, splicing, nuclear-cytoplasmic transport, and R-loop metabolism. Based on analysis of these data, we suggest that m6A methylation of nuclear RNAs is another level of gene expression regulation which, together with DNA methylation and histone modifications, controls chromatin structure and functioning in various biological contexts.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Abbreviations

m6A:

N6-methyladenosine

mRNA:

messenger RNA

References

  1. Boccaletto, P., Machnicka, M. A., Purta, E., Piatkowski, P., Baginski, B., et al. (2018) MODOMICS: a database of RNA modification pathways. 2017 update, Nucleic Acids Res., 46, 303-307, https://doi.org/10.1093/nar/gkx1030.

    Article  CAS  Google Scholar 

  2. Frye, M., Harada, B. T., Behm, M., and He, C. (2018) RNA modifications modulate gene expression during development, Science, 361, 1346-1349, https://doi.org/10.1126/science.aau1646.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  3. Desrosiers, R., Friderici, K., and Rottman, F. (1974) Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells, Proc. Natl. Acad. Sci. USA, 10, 3971-3975, https://doi.org/10.1073/pnas.71.10.3971.

    Article  ADS  Google Scholar 

  4. Perry, R. P., and Kelley, D. E. (1974) Existence of methylated messenger RNA in mouse L cells, Cell, 1, 37-42, https://doi.org/10.1016/0092-8674(74)90153-6.

    Article  CAS  Google Scholar 

  5. Meyer, K. D., Saletore, Y., Zumbo, P., Elemento, O., Mason, C. E., et al. (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons, Cell, 149, 1635-1646, https://doi.org/10.1016/j.cell.2012.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dominissini, D., Moshitch-Moshkovitz, S., Schwartz, S., Salmon-Divon, M., Ungar, L., et al. (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq, Nature, 485, 201-206, https://doi.org/10.1038/nature11112.

    Article  CAS  PubMed  ADS  Google Scholar 

  7. Deng, X., Chen, K., Luo, G. Z., Weng, X., Ji, Q., et al. (2015) Widespread occurrence of N6-methyladenosine in bacterial mRNA, Nucleic Acids Res., 43, 6557-6567, https://doi.org/10.1093/nar/gkv596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Clancy, M. J., Shambaugh, M. E., Timpte, C. S., and Bokar, J. A. (2002) Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA: a potential mechanism for the activity of the IME4 gene, Nucleic Acids Res., 30, 4509-4518, https://doi.org/10.1093/nar/gkf573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lence, T., Akhtar, J., Bayer, M., Schmid, K., Spindler, L., et al. (2016) m6A modulates neuronal functions and sex determination in drosophila, Nature, 540, 242-247, https://doi.org/10.1038/nature20568.

    Article  CAS  PubMed  ADS  Google Scholar 

  10. Luo, G. Z., MacQueen, A., Zheng, G., Duan, H., Dore, L. C., et al. (2014) Unique features of the m6A methylome in arabidopsis thaliana, Nat. Commun., 5, 5630, https://doi.org/10.1038/ncomms6630.

    Article  CAS  PubMed  ADS  Google Scholar 

  11. Schibler, U., and Perry, R. P. (1977) The 50-termini of heterogeneous nuclear RNA: a comparison among molecules of different sizes and ages, Nucleic Acids Res., 4, 4133-4149, https://doi.org/10.1093/nar/4.12.4133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wei, C.-M., and Moss, B. (1977) Nucleotide sequences at the N6-methylade-nosine sites of HeLa cell messenger ribonucleic acid, Biochemistry, 16, 1672-1676, https://doi.org/10.1021/bi00627a023.

    Article  CAS  PubMed  Google Scholar 

  13. Liu, N., and Pan, T. (2016) N6-methyladenosine-encoded epitranscriptomics, Nat. Struct. Mol. Biol., 23, 98-102, https://doi.org/10.1038/nsmb.3162.

    Article  CAS  PubMed  Google Scholar 

  14. Ke, S., Alemu, E. A., Mertens, C., Gantman, E. C., Fak, J. J., et al. (2015) A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation, Genes Dev., 29, 2037-2053, https://doi.org/10.1101/gad.269415.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shimba, S., Bokar, J. A., Rottman, F., and Reddy, R. (1995) Accurate and efficient N-6-adenosine methylation in spliceosomal U6 small nuclear RNA by HeLa cell extract in vitro, Nucleic Acids Res., 23, 2421-2426, https://doi.org/10.1093/nar/23.13.2421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Patil, D. P., Chen, C. K., Pickering, B. F., Chow, A., Jackson, C., et al. (2016) m6A RNA methylation promotes XIST-mediated transcriptional repression, Nature, 537, 369-373, https://doi.org/10.1038/nature19342.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  17. Piekna-Przybylska, D., Decatur, W. A., and Fournier, M. J. (2008) The 3D rRNA modification maps database: with interactive tools for ribosome analysis, Nucleic Acids Res., 36, 178-183, https://doi.org/10.1093/nar/gkm855.

    Article  CAS  Google Scholar 

  18. Konstantinos, B., and Lieberman, E. (2023) Biological roles of adenine methylation in RNA, Nat. Rev. Genet., 3, 143-160, https://doi.org/10.1038/s41576-022-00534-0.

    Article  CAS  Google Scholar 

  19. Ma, Z., and Ji, J. (2020) N6-methyladenosine (m6A) RNA modification in cancer stem cells, Stem Cells, 38, 1511-1519, https://doi.org/10.1002/stem.3279.

    Article  CAS  Google Scholar 

  20. Roundtree, I. A., Evans, M. E., Pan, T., and He, C. (2017) Dynamic RNA modifications in gene expression regulation, Cell, 169, 1187-1200, https://doi.org/10.1016/j.cell.2017.05.045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sledz, P., and Jinek, M. (2016) Structural insights into the molecular mechanism of the m(6)A writer complex, Elife, 5, e18434, https://doi.org/10.7554/eLife.18434.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wang, P., Doxtader, K. A., and Nam, Y. (2016) Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases, Mol. Cell, 63, 306-317, https://doi.org/10.1016/j.molcel.2016.05.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ping, X. L., Sun, B. F., Wang, L., Xiao, W., Yang, X., et al. (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase, Cell Res., 24, 177-189, https://doi.org/10.1038/cr.2014.3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huang, Q., Mo, J., Liao, Z., Chen, X., and Zhang, B. (2022) The RNA m6A writer WTAP in diseases: structure, roles, and mechanisms, Cell Death Disease, 13, 852, https://doi.org/10.1038/s41419-022-05268-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang, X., Lu, Z., Gomez, A., Hon, G. C., Yue, Y., et al. (2014) N6-methyladenosine-dependent regulation of messenger RNA stability, Nature, 505, 117-120, https://doi.org/10.1038/nature12730.

    Article  CAS  PubMed  ADS  Google Scholar 

  26. Wang, X., Zhao, B. S., Roundtree, I. A., Lu, Z., Han, D., et al. (2015) N(6)-methyladenosine modulates messenger RNA translation efficiency, Cell, 161, 1388-1399, https://doi.org/10.1016/j.cell.2015.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Meyer, K. D., Patil, D. P., Zhou, J., Zinoviev, A., Skabkin, M. A., et al. (2015) 5′ UTR m(6)A promotes cap-independent translation, Cell, 163, 999-1010, https://doi.org/10.1016/j.cell.2015.10.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sun, W., Ming, S. T., Wu, R., and Ming, L. (2019) The role of m6A RNA methylation in cancer, Biomed. Pharmacother., 112, 108613, https://doi.org/10.1016/j.biopha.2019.108613.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, Y., Zhang, S.., Shi, M., Li, M., Zeng, J., et al. (2022) Roles of m6A modification in neurological diseases, Zhong Nan Da Xue Xue Bao Yi Xue Ban., 47, 109-115.

    PubMed  Google Scholar 

  30. Ivanova, I., Much, C., Di Giacomo, M., Azzi, C., Morgan, M., et al. (2017) The RNA m6A reader YTHDF2 is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence, Mol. Cell, 67, 1059-1067.e4, https://doi.org/10.1016/j.molcel.2017.08.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Geula, S., Moshitch-Moshkovitz, S., Dominissini, D., Mansour, A. A. F., Kol, N., et al. (2015) m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation, Science, 347, 1002-1006, https://doi.org/10.1126/science.1261417.

    Article  CAS  PubMed  ADS  Google Scholar 

  32. Li, H. B., Tong, J., Zhu, S., Batista, P. J., Duffy, E. E., Zhao, J., et al. (2017) m(6)A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways, Nature, 548, 338-342, https://doi.org/10.1038/nature23450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, X., Tian, L., Li, Y., Wang, J., Yan, B., et al. (2021) RBM15 facilitates laryngeal squamous cell carcinoma progression by regulating TMBIM6 stability through IGF2BP3 dependent, J. Exp. Clin. Cancer Res., 40, 80, https://doi.org/10.1186/s13046-021-01871-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang, W., Chen, Y., Zeng, Z., Peng, Y., Li, L., et al. (2022) The novel m6A writer METTL5 as prognostic biomarker probably associating with the regulation of immune microenvironment in kidney cancer, Heliyon, 8, e12078, https://doi.org/10.1016/j.heliyon.2022.e12078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pendleton, K. E., Chen, B., Liu, K., Hunter, O. V., Xie, Y., et al. (2017) The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention, Cell, 169, 824-835.e14, https://doi.org/10.1016/j.cell.2017.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mendel, M., Chen, K. M., Homolka, D., Gos, P., Pandey, R. R., et al. (2018) Methylation of structured RNA by the m6A Writer METTL16 is essential for mouse embryonic development, Mol. Cell, 71, 986-1000.e11, https://doi.org/10.1016/j.molcel.2018.08.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Doxtader, K. A., Wang, P., Scarborough, A. M., Seo, D., Conrad, N. K., et al. (2018) Structural basis for regulation of METTL16, an S-adenosylmethionine homeostasis factor, Mol. Cell, 71, 1001-1011.e4., https://doi.org/10.1016/j.molcel.2018.07.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang, D., Zhao, G., and Zhang, H. M. (2023) m6A reader proteins: the executive factors in modulating viral replication and host immune response, Front. Cell. Infect. Microbiol., 13, 1-20, https://doi.org/10.3389/fcimb.2023.1151069.

    Article  CAS  Google Scholar 

  39. Guo, T., Duan, H., Chen, J., Liu, J., Othmane, B., et al. (2021) N6-methyladenosine writer gene ZC3H13 predicts immune phenotype and therapeutic opportunities in kidney renal clear cell carcinoma, Front. Oncol., 11, 718644, https://doi.org/10.3389/fonc.2021.718644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang, X., Li, M. J., Xia, L., and Zhang, H. (2022) The biological function of m6A methyltransferase KIAA1429 and its role in human disease, PeerJ, 10, e14334, https://doi.org/10.7717/peerj.14334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jia, G., Fu, Y., Zhao, X., Dai, Q., Zheng, G., et al. (2011) N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO, Nat. Chem. Biol., 7, 885-887, https://doi.org/10.1038/nchembio.687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zheng, G., Dahl, J. A., Niu, Y., Fedorcsak, P., Huang, C.-M., et al. (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility, Mol. Cell, 49, 18-29, https://doi.org/10.1016/j.molcel.2012.10.015.

    Article  CAS  PubMed  Google Scholar 

  43. Wei, J., Liu, F., Lu, Z., Fei, Q., Ai, Y., et al. (2018) Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm, Mol. Cell, 71, 973-985.e975, https://doi.org/10.1016/j.molcel.2018.08.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kaur, S., Tam, N. Y., McDonough, M. A., Schofield, C. J., and Aik, W. S. (2022) Mechanisms of substrate recognition and N6-methyladenosine demethylation revealed by crystal structures of ALKBH5-RNA complexes, Nucleic Acids Res., 50, 4148-4160, https://doi.org/10.1093/nar/gkac195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Panneerdoss, S., Eedunuri, V. K., Yadav, P., Timilsina, S., Rajamanickam, S., et al. (2018) Cross-talk among writers, readers, and erasers of m(6)A regulates cancer growth and progression, Sci. Adv., 4, 1-15, https://doi.org/10.1126/sciadv.aar8263.

    Article  CAS  Google Scholar 

  46. Zhang, C., Samanta, D., Lu, H., Bullen, J. W., Zhang, H., et al. (2016) Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOG mRNA, Proc. Natl. Acad. Sci. USA, 113, E2047-E2056, https://doi.org/10.1073/pnas.1602883113.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Shi, H., Wang, X., Lu, Z., Zhao, B. S., Ma, H., et al. (2017) YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA, Cell Res., 27, 315-328, https://doi.org/10.1038/cr.2017.15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Alarcón, C. R., Goodarzi, H., Lee, H., Liu, X., Tavazoie, S., et al. (2015) HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events, Cell, 162, 1299-1308, https://doi.org/10.1016/j.cell.2015.08.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang, H., Weng, H., Sun, W., Qin, X., Shi, H., et al. (2018) Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation, Nat. Cell Biol., 20, 285-295, https://doi.org/10.1038/s41556-018-0045-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Han, D., Liu, J., Chen, C., Dong, L., Liu, Y., et al. (2019) Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells, Nature, 566, 270-274, https://doi.org/10.1038/s41586-019-0916-x.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  51. Liu, N., Zhou, K. I., Parisien, M., Dai, Q., Diatchenko, L., et al. (2017) N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein, Nucleic Acids Res., 45, 6051-6063, https://doi.org/10.1093/nar/gkx141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zaccara, S. and Jaffrey, S. R. (2020) A unified model for the function of YTHDF proteins in regulating m6A-modified mRNA, Cell, 181, 1582-1595, https://doi.org/10.1016/j.cell.2020.05.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shi, H., Zhang, X., Weng, Y. L., Lu, Z., Liu, Y., et al. (2018) m(6)A facilitates hippocampus-dependent learning and memory through YTHDF1, Nature, 563, 249-253, https://doi.org/10.1038/s41586-018-0666-1.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  54. Anders, M., Chelysheva, I., Goebel, I., Trenkner, T., Zhou, J., et al. (2018) Dynamic m6A methylation facilitates mRNA triaging to stress granules, Life Sci. Alliance, 1, e201800113, https://doi.org/10.26508/lsa.201800113.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Li, X., Xiong, X., and Yi, C. (2016) Epitranscriptome sequencing technologies: decoding RNA modifications, Nat. Methods, 14, 23-31, https://doi.org/10.1038/nmeth.4110.

    Article  CAS  PubMed  Google Scholar 

  56. Hartmann, A. M., Nayler, O., Schwaiger, F. W., Obermeier, A., and Stamm, S. (1999) The interaction and colocalization of Sam68 with the splicing-associated factor YT521-B in nuclear dots is regulated by the Src family kinase p59(fyn), Mol. Biol. Cell, 10, 3909-3926, https://doi.org/10.1091/mbc.10.11.3909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kasowitz, S. D., Ma, J., Anderson, S. J., Leu, N. A., Xu, Y., et al. (2018) Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development, PLoS Genet., 14, 1-28, https://doi.org/10.1371/journal.pgen.1007412.

    Article  CAS  Google Scholar 

  58. Liu, J., Dou, X., Chen, C., Chen, C., Liu, C., et al. (2020) N6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription, Science, 367, 580-586, https://doi.org/10.1126/science.aay6018.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  59. Wojtas, M. N., Pandey, R. R., Mendel, M., Homolka, D., Sachidanandam, R., et al. (2017) Regulation of m6A transcripts by the 3′→5′ RNA helicase YTHDC2 is essential for a successful meiotic program in the mammalian germline, Mol. Cell, 68, 374-387.e12, https://doi.org/10.1016/j.molcel.2017.09.021.

    Article  CAS  PubMed  Google Scholar 

  60. Liu, N.., Dai, Q., Zheng, G., He, C., Parisien, M., et al. (2015) N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions, Nature, 518, 560-564, https://doi.org/10.1038/nature14234.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  61. Sun, M., Shen, Y., Jia, G., Deng, Z., Shi, F., et al. (2023) Activation of the HNRNPA2B1/miR-93-5p/FRMD6 axis facilitates prostate cancer progression in an m6A-dependent manner, J. Cancer, 14, 1242-1256, https://doi.org/10.7150/jca.83863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shatkin, A., and Manley, J. (2000) The ends of the affair: capping and polyadenylation, Nat. Struct. Biol., 7, 1-5, https://doi.org/10.1038/79583.

    Article  CAS  Google Scholar 

  63. Salditt-Georgieff, M., Jelinek, W., Darnell, J. E., Furuichi, Y., Morgan, M., et al. (1976) Methyl labeling of HeLa cell hnRNA: a comparison with mRNA, Cell, 2, 227-237, https://doi.org/10.1016/0092-8674(76)90022-2.

    Article  Google Scholar 

  64. Carroll, S. M., Narayan, P., and Rottman, F. M. (1990) N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA, Mol. Cell. Biol., 10, 4456-4465, https://doi.org/10.1128/mcb.10.9.4456-4465.1990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Haussmann, I. U., Bodi, Z., Sanchez-Moran, E., Mongan, N. P., Archer, N., et al. (2016) m6A potentiates Sxl alternative pre- mRNA splicing for robust Drosophila sex determination, Nature, 540, 301-304, https://doi.org/10.1038/nature20577.

    Article  CAS  PubMed  ADS  Google Scholar 

  66. Xiao, W., Adhikari, S., Dahal, U., Chen, Y. S., Hao, Y. J., et al. (2016) Nuclear m6A reader YTHDC1 regulates mRNA splicing, Mol. Cell, 61, 507-519, https://doi.org/10.1016/j.molcel.2016.01.012.

    Article  CAS  PubMed  Google Scholar 

  67. Xu, K., Yang, Y., Feng, G. H., Sun, B. F., Chen, J. Q., et al. (2017) Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation, Cell Res., 9, 1100-1114, https://doi.org/10.1038/cr.2017.100.

    Article  CAS  Google Scholar 

  68. Zhao, X., Yang, Y., Sun, B. F., Shi, Y., Yang, X., et al. (2014) FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis, Cell Res., 24, 1403-1419, https://doi.org/10.1038/cr.2014.151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Finkel, D., and Groner, Y. (1983) Methylations of adenosine residues (m6A) in pre-mRNA are important for formation of late simian virus 40 mRNAs, Virology, 131, 409-425, https://doi.org/10.1016/0042-6822(83)90508-1.

    Article  CAS  PubMed  Google Scholar 

  70. Lesbirel, S., and Wilson, S. A. (2019) The m6Amethylase complex and mRNA export, Biochim. Biophys. Acta Gene Regul. Mech., 3, 319-328, https://doi.org/10.1016/j.bbagrm.2018.09.008.

    Article  CAS  Google Scholar 

  71. Viphakone, N., Hautbergue, G. M., Walsh, M., Chang, C.-T., Holland, A., et al. (2012) TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export, Nat. Commun., 3, 1006, https://doi.org/10.1038/ncomms2005.

    Article  CAS  PubMed  ADS  Google Scholar 

  72. Masuda, S., Das, R., Cheng, H., Hurt, E., Dorman, N., and Reed, R. (2005) Recruitment of the human TREX complex to mRNA during splicing, Genes Dev., 19, 1512-1517, https://doi.org/10.1101/gad.1302205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Roundtree, I. A., Luo, G.-Z., Zhang, Z., Wang, X., Zhou, T., et al. (2017) YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs, eLife, 6, e31311, https://doi.org/10.7554/eLife.31311.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Muller-McNicoll, M., Botti, V., de Jesus Domingues, A. M., Brandl, H., Schwich, O. D., et al. (2016) SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export, Genes Dev., 30, 553-566, https://doi.org/10.1101/gad.276477.115.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zheng, Q., Hou, J., Zhou, Y., Li, Z., and Cao, X. (2017) The RNA helicase DDX46 inhibits innate immunity by entrapping m(6)A-demethylated antiviral transcripts in the nucleus, Nat. Immunol., 18, 1094-1103, https://doi.org/10.1038/ni.3830.

    Article  CAS  PubMed  Google Scholar 

  76. Thiery, J. P., Acloque, H., Huang, R. Y. J., and Nieto, M. A. (2009) Epithelial-mesenchymal transitions in development and disease, Cell, 139, 871-890, https://doi.org/10.1016/j.cell.2009.11.007.

    Article  CAS  PubMed  Google Scholar 

  77. Lin, X., Chai, G., Wu, Y., Li, J., Chen, F., et al. (2019) RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail, Nat. Commun., 10, 2065, https://doi.org/10.1038/s41467-019-09865-9.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  78. Fustin, J. M., Doi, M., Yamaguchi, Y., Hida, H., Nishimura, S., et al. (2013) RNA-methylation-dependent RNA processing controls the speed of the circadian clock, Cell, 155, 793-806, https://doi.org/10.1016/j.cell.2013.10.026.

    Article  CAS  PubMed  Google Scholar 

  79. Du, H., Zhao, Y., He, J., Zhang, Y., Xi, H., et al. (2016) YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex, Nat. Commun., 7, 12626, https://doi.org/10.1038/ncomms12626.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  80. Li, X., and Fu, X. D. (2019) Chromatin-associated RNAs as facilitators of functional genomic interactions, Nat. Rev. Genet., 20, 503-519, https://doi.org/10.1038/s41556-018-0045-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lee, J. H., Wang, R., Xiong, F., Krakowiak, J., Liao, Z., et al. (2021) Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation, Mol. Cell, 81, 3368-3385, https://doi.org/10.1016/j.molcel.2021.07.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang, K. C., and Chang, H. Y. (2011) Molecular mechanisms of long noncoding RNAs, Mol. Cell, 43, 904-914, https://doi.org/10.1016/j.molcel.2011.08.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sahakyan, A., Yang, Y., and Plath, K. (2018) The role of Xist in X-chromosome dosage compensation, Trends Cell Biol., 28, 999-1013, https://doi.org/10.1016/j.tcb.2018.05.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Li, Y., Xia, L., Tan, K., Ye, X., Zuo, Z., et al. (2020) N6-methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2, Nat. Genet., 52, 870-877, https://doi.org/10.1038/s41588-020-0677-3.

    Article  CAS  PubMed  Google Scholar 

  85. Liu, X. M., Mao, Y., Wang, S., Zhou, J., and Qian, S. B. (2022) METTL3 modulates chromatin and transcription dynamics during cell fate transition, Cell. Mol. Life Sci., 79, 559, https://doi.org/10.1007/s00018-022-04590-x.

    Article  CAS  PubMed  Google Scholar 

  86. Wei, J., Yu, X., Yang, L., Liu, X., Gao, B., et al. (2022) FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development, Science, 376, 968-973, https://doi.org/10.1126/science.abe9582.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  87. Fernández-Justel, J. M., Santa-María, C., Martín-Vírgala, S., Ramesh, S., Ferrera-Lagoa, A., et al. (2022) Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner, Cell Rep., 40, 111329, https://doi.org/10.1016/j.celrep.2022.111329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sun, T., Xu, Y., Xiang, Y., Ou, J., Soderblom, E. J., et al. (2023) Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells, Nat. Genet., 55, 1324-1335, https://doi.org/10.1038/s41588-023-01452-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sanz, L. A., Hartono, S. R., Lim, Y. W., Steyaert, S., Rajpurkar, A., et al. (2016) Prevalent, dynamic, and conserved R-loop structures associate with specific epigenomic signatures in mammals, Mol. Cell, 1, 167-178, https://doi.org/10.1016/j.molcel.2016.05.032.

    Article  CAS  Google Scholar 

  90. Wahba, L., Costantino, L., Tan, F. J., Zimmer, A., and Koshland, D. (2016) S1-DRIP-seq identifies high expression and polyA tracts as major contributors to R-loop formation, Genes Dev., 11, 1327-1338, https://doi.org/10.1101/gad.280834.116.

    Article  CAS  Google Scholar 

  91. Xu, W., Xu, H., Li, K., Fan, Y., Liu, Y., et al. (2017) The R-loop is a common chromatin feature of the Arabidopsis genome, Nat. Plants, 9, 704-714, https://doi.org/10.1038/s41477-017-0004-x.

    Article  CAS  Google Scholar 

  92. Kornberg, A., and Baker, T. A. (1992) DNA Replication, Vol. 3, W. H. Freeman and Co., NY.

  93. Gowrishankar, J., Leela, J. K., and Anupama, K. (2013) R-loops in bacterial transcription: their causes and consequences, Transcription, 4, 153-157, https://doi.org/10.4161/trns.25101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ginno, P. A., Lott, P. L., Christensen, H. C., Korf, I., and Chédin, F. (2012) R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters, Mol. Cell, 45, 814-825, https://doi.org/10.1016/j.molcel.2012.01.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nadel, J., Athanasiadou, R., Lemetre, C., Wijetunga, N. A., Broin, Ó. P., et al. (2015) RNA:DNA hybrids in the human genome have distinctive nucleotide characteristics, chromatin composition, and transcriptional relationships, Epigenetics Chromatin, 8, 46, https://doi.org/10.1186/s13072-015-0040-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pfeiffer, V., Crittin, J., Grolimund, L., and Lingner, J. (2013) The THO complex component Thp2 counteracts telomeric R-loops and telomere shortening, EMBO J., 21, 2861-2871, https://doi.org/10.1038/emboj.2013.217.

    Article  CAS  Google Scholar 

  97. El Hage, A., Webb, S., Kerr, A., and Tollervey, D. (2014) Genome-wide distribution of RNA-DNA hybrids identifies RNase H targets in tRNA genes, retrotransposons and mitochondria, PLoS Genet., 10, e1004716, https://doi.org/10.1371/journal.pgen.1004716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Aguilera, A., and García-Muse, T. (2012) R-loops: from transcription byproducts to threats to genome stability, Mol. Cell, 46, 115-124, https://doi.org/10.1016/j.molcel.2012.04.009.

    Article  CAS  PubMed  Google Scholar 

  99. Skourti-Stathaki, K., and Proudfoot, N. J. (2014) A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression, Genes Dev., 28, 1384-1396, https://doi.org/10.1101/gad.242990.114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sollier, J., and Cimprich, K. A. (2015) Breaking bad: R-loops and genome integrity, Trends Cell Biol., 9, 514-522, https://doi.org/10.1016/j.tcb.2015.05.003.

    Article  CAS  Google Scholar 

  101. Chen, L., Chen, J. Y., Zhang, X., Gu, Y., Xiao, R., et al. (2017) R-ChIP using inactive RNase H reveals dynamic coupling of R-loops with transcriptional pausing at gene promoters, Mol. Cell, 68, 745-757, https://doi.org/10.1016/j.molcel.2017.10.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Santos-Pereira, J. M., and Aguilera, A. (2015) R loops: new modulators of genome dynamics and function, Nat. Rev. Genet., 10, 583-597, https://doi.org/10.1038/nrg3961.

    Article  CAS  Google Scholar 

  103. Chédin, F. (2016) Nascent connections: R-loops and chromatin patterning, Trends Genet., 12, 828-838, https://doi.org/10.1016/j.tig.2016.10.002.

    Article  CAS  Google Scholar 

  104. Lu, W. T., Hawley, B. R., Skalka, G. L., Baldock, R. A., Smith, E. M., et al. (2018) Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair, Nat. Commun., 1, 532, https://doi.org/10.1038/s41467-018-02893-x.

    Article  CAS  ADS  Google Scholar 

  105. Kogoma, T. (1997) Stable DNA replication: interplay between DNA replication, homologous recombination, and transcription, Microbiol. Mol. Biol. Rev., 2, 212-223, https://doi.org/10.1128/mmbr.61.2.212-238.1997.

    Article  CAS  Google Scholar 

  106. Massé, E., and Drolet, M. (1999) Escherichia coli DNA topoisomerase I inhibits R-loop formation by relaxing transcription-induced negative supercoiling, J. Biol. Chem., 23, 16659-16664, https://doi.org/10.1074/jbc.274.23.16659.

    Article  Google Scholar 

  107. Massé, E., and Drolet, M. (1999) R-loop-dependent hypernegative supercoiling in Escherichia coli topA mutants preferentially occurs at low temperatures and correlates with growth inhibition, J. Mol. Biol., 2, 321-332, https://doi.org/10.1006/jmbi.1999.3264.

    Article  CAS  Google Scholar 

  108. Abakir, A., Giles, T. C., Cristini, A., Foster, J. M., Dai, N., et al. (2020) N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells, Nat. Genet., 1, 48-55, https://doi.org/10.1038/s41588-019-0549-x.

    Article  CAS  Google Scholar 

  109. Salas-Armenteros, I., Pérez-Calero, C., Bayona-Feliu, A., Tumini, E., Luna, R., et al. (2017) Human THO-Sin3A interaction reveals new mechanisms to prevent R-loops that cause genome instability, EMBO J., 23, 3532-3547, https://doi.org/10.15252/embj.201797208.

    Article  CAS  Google Scholar 

  110. Wei, J., and He, C. (2021) Chromatin and transcriptional regulation by reversible RNA methylation, Curr. Opin. Cell Biol., 70, 109-115, https://doi.org/10.1016/j.ceb.2020.11.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yang, X., Liu, Q. L., Xu, W., Zhang, Y. C., Yang, Y., et al. (2019) m6A promotes R-loop formation to facilitate transcription termination, Cell Res., 12, 1035-1038, https://doi.org/10.1038/s41422-019-0235-7.

    Article  CAS  Google Scholar 

  112. Duda, K. J., Ching, R. W., Jerabek, L., Shukeir, N., Erikson, G., et al. (2021) m6A RNA methylation of major satellite repeat transcripts facilitates chromatin association and RNA:DNA hybrid formation in mouse heterochromatin, Nucleic Acids Res., 249, 5568-5587, https://doi.org/10.1093/nar/gkab364.

    Article  CAS  Google Scholar 

  113. Chen, L., Zhang, C., Ma, W., Huang, J., Zhao, Y., et al. (2022) METTL3-mediated m6A modification stabilizes TERRA and maintains telomere stability, Nucleic Acids Res., 50, 11619-11634, https://doi.org/10.1093/nar/gkac1027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ying, Y., Tang, Y., Wu, Y., Yi, J., Liu, Z., et al. (2023) Epigenetic regulation of co-transcriptional R-loops via IGF2BPs drives SEMA3F-mediated prostate cancer growth retardation and docetaxel chemosensitivity enhancement, Research Square, https://doi.org/10.21203/rs.3.rs-3111467/v1.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The work was supported by the Russian Science Foundation (grant no. 22-65-00022) and by the Ministry of Science and Higher Education of the Russian Federation (State Assignment no. 122 0411001149-7), “Introduction” section.

Author information

Authors and Affiliations

  1. Institute of Bioengineering, Research Center of Biotechnology, Russian Academy of Sciences, 119071, Moscow, Russia

    Nadezhda A. Zhigalova, Katerina Yu. Oleynikova, Alexey S. Ruzov & Alexander S. Ermakov

  2. Faculty of Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    Alexander S. Ermakov

Authors
  1. Nadezhda A. Zhigalova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katerina Yu. Oleynikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexey S. Ruzov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander S. Ermakov
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.S.E. developed the concept of the review; N.A.Zh., K.Yu.O., A.S.R., and A.S.E. collected and discussing literary data and wrote the article; N.A.Zh., and A.S.E. prepared illustrations, K.Yu.O., A.S.R., and A.S.E. edited the manuscript.

Corresponding author

Correspondence to Alexander S. Ermakov.

Ethics declarations

This work does not contain any studies involving human and animal subjects. The authors of this work declare that they have no conflicts of interest.

Additional information

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhigalova, N.A., Oleynikova, K.Y., Ruzov, A.S. et al. The Functions of N6-Methyladenosine in Nuclear RNAs. Biochemistry Moscow 89, 159–172 (2024). https://doi.org/10.1134/S0006297924010103

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297924010103

Keywords

Search

Navigation