Posttranskripsiyonel RNA modifikasyonları ve fonksiyonları

Öz

Transkripsiyon sonrası mRNA modifikasyonları, posttranskripsiyonel RNA modifikasyonları, RNA epigenetiği ya da epitranskriptomiks olarak adlandırılmaktadır. RNA'da DNA’ya göre daha fazla modifikasyon olmaktadır, çünkü DNA genetik bilgi deposu iken RNA mRNA, rRNA, tRNA, miRNA gibi farklı türlerine ve farklı katalitik, gen düzenleme, protein sentezi gibi fonksiyonlara sahiptir. RNA’da posttranskripsiyonel modifikasyonlar yaklaşık 60 yıl önce Psödoouridinin (Ψ) tanımlanması ile keşfedildi. RNA'larda gözlenen 3 majör modifikasyon, 2’-0-metil nükleotit, 5-metilsitozin (m5C) ve N6-metil adenindir (m6A). m6A modifikasyonunun embriyonik ve nöral kök hücrelerin farklılaşmasında önemli bir rol oynadığı bulunmuştur. RNA'da posttranskripsiyonel modifikasyonları yeni bir alan olup biyolojik önemini anlamak için yeni çalışmalara ihtiyaç duyulmaktadır.

Anahtar Kelimeler

• Epigenetik
• RNA
• 5-metilsitozin (m5C)
• N6-metil adenin

Posttranscriptional RNA modifications and functions

Öz

Post transcriptional mRNA modifications are called epitranscriptomics or RNA epigenetics. There are more modifications in RNA than DNA because the DNA is a genetic information store, while RNA has different types of mRNAs including mRNA, rRNA, tRNA, miRNA, and different catalytic, gene regulation, protein synthesis functions. Identification of pseudouridine (Ψ) was discovered about 60 years ago. Three major modifications observed in RNAs are 2’-O-methyl nucleotide, 5-methylcytosine (m5C) and N6-methyl adenosine. m6A modification has been found to play an important role in the differentiation of embryonic stem cells and nerve cell. RNA epigenetics studies are a very new area and require many more studies to understand its biological significance.

Anahtar Kelimeler

• Epigenetic
• RNA
• 5-methylcytosine (m5C)
• N6-methyl adenosine

Kaynakça

1. Angelova, M. T., Dimitrova, D. G., Dinges, N., Lence, T., Worpenberg, L., Carré, C., & Roignant, J. Y. (2018). The emerging field of epitranscriptomics in neurodevelopmental and neuronal disorders. Frontiers in Bioengineering and Biotechnology, 6, 46.
2. Batista, P. J., Molinie, B., Wang, J., Qu, K., Zhang, J., Li, L., ... & Carter, A. C. (2014). m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell, 15(6), 707-719.
3. Beaudry, A. A., & Joyce, G. F. (1992). Directed evolution of an RNA enzyme. Science, 257 (5070), 635-641.
4. Dominissini D, Chuan H, Rechavı G, Moshitch S. (2016). RNA epigenetics. Scientist. 30(1): 34-39.
5. Fustin, J. M., Doi, M., Yamaguchi, Y., Hida, H., Nishimura, S., Yoshida, M., ... & Okamura, H. (2013). RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell, 155(4), 793-806.
6. Frye, M., Harada, B. T., Behm, M., & He, C. (2018). RNA modifications modulate gene expression during development. Science, 361(6409), 1346-1349.
7. Gregory, R. I., Chendrimada, T. P., Cooch, N., & Shiekhattar, R. (2005). Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell, 123(4), 631-640.
8. He, Y., Hu, H., Wang, Y., Yuan, H., Lu, Z., Wu, P., ... & Miao, Y. (2018). ALKBH5 inhibits pancreatic cancer motility by decreasing long non-coding RNA KCNK15-AS1 methylation. Cellular Physiology and Biochemistry, 48(2), 838-846.

9. Jalkanen, A. L., & Wilusz, J. (2014). Stem cell RNA epigenetics: M6Arking your territory. Cell Stem Cell, 15(6), 669-670.
10. Jäschke, A., & Seelig, B. (2000). Evolution of DNA and RNA as catalysts for chemical reactions. Current Opinion in Chemical Biology, 4(3), 257-262. Ji, P., Wang, X., Xie, N., & Li, Y. (2018). N6-Methyladenosine in RNA and DNA: an epitranscriptomic and epigenetic player implicated in determination of stem cell fate. Stem Cells International, 2018, 3256524.
11. Jia, G., Fu, Y., Zhao, X., Dai, Q., Zheng, G., Yang, Y., ... & He, C. (2011). N 6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature Chemical Biology, 7(12), 885-887.
12. Khoddami, V., Yerra, A., & Cairns, B. R. (2015). Experimental approaches for target profiling of RNA cytosine methyltransferases. In Methods in Enzymology (Vol. 560, pp. 273-296). Academic Press.
13. Leighton, L. J., Ke, K., Zajaczkowski, E. L., Edmunds, J., Spitale, R. C., & Bredy, T. W. (2018). Experience‐dependent neural plasticity, learning, and memory in the era of epitranscriptomics. Genes, Brain and Behavior, 17(3), e12426. Li, M., Zhao, X., Wang, W., Shi, H., Pan, Q., Lu, Z., ... & Klungland, A. (2018). Ythdf2-mediated m 6 A mRNA clearance modulates neural development in mice. Genome Biology, 19(1), 1-16.
14. Liu, N., & Pan, T. (2015). RNA epigenetics. Translational Research, 165(1), 28–35.
15. Meyer, K. D., Saletore, Y., Zumbo, P., Elemento, O., Mason, C. E., & Jaffrey, S. R. (2012). Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell, 149(7), 1635-1646.
16. Meyer, K. D., & Jaffrey, S. R. (2014). The dynamic epitranscriptome: N 6-methyladenosine and gene expression control. Nature Reviews Molecular Cell Biology, 15(5), 313-326.
17. Motorin, Y., Lyko, F., & Helm, M. (2010). 5-methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Research, 38(5), 1415-1430.
18. Roundtree, I. A., & He, C. (2016). RNA epigenetics-chemical messages for posttranscriptional gene regulation. Current Opinion in Chemical Biology, 30, 46-51.
19. Sole, R. V. (2009). Evolution and self-assembly of protocells. The International Journal of Biochemistry & Cell Biology, 41(2), 274-284.
20. Steitz, T. A., & Moore, P. B. (2003). RNA, the first macromolecular catalyst: the ribosome is a ribozyme. Trends in Biochemical Sciences, 28(8), 411-418.
21. Shi, H., Wei, J., & He, C. (2019). Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Molecular Cell, 74(4), 640-650.
22. Wang, C. X., Cui, G. S., Liu, X., Xu, K., Wang, M., Zhang, X. X., ... & Sun, B. F. (2018). METTL3- mediated m6A modification is required for cerebellar development. PLoS Biology, 16(6), e2004880.
23. Wang, S., Chai, P., Jia, R., & Jia, R. (2018). Novel insights on m 6 A RNA methylation in tumorigenesis: a double-edged sword. Molecular Cancer, 17(1), 101.
24. Weng, H., Huang, H., Wu, H., Qin, X., Zhao, B. S., Dong, L., ... & Sheng, Y. (2018). METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification. Cell Stem Cell, 22(2), 191-205.
25. Yang, F., Jin, H., Que, B., Chao, Y., Zhang, H., Ying, X., ... & Zhang, W. (2019). Dynamic m 6 A mRNA methylation reveals the role of METTL3-m 6 A-CDCP1 signaling axis in chemical carcinogenesis. Oncogene, 38(24), 4755-4772.
26. Yao, B., Christian, K. M., He, C., Jin, P., Ming, G. L., & Song, H. (2016). Epigenetic mechanisms in neurogenesis. Nature Reviews Neuroscience, 17(9), 537-549.
27. Zhao, X., & Yu, Y. T. (2008). Targeted pre-mRNA modification for gene silencing and regulation. Nature Methods, 5(1), 95-100.
28. Zheng, G., Dahl, J. A., Niu, Y., Fedorcsak, P., Huang, C. M., Li, C. J., ... & Lu, Z. (2013). ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Molecular Cell, 49(1), 18-29.
29. Zhou, R., Gao, Y., Lv, D., Wang, C., Wang, D., & Li, Q. (2019). METTL3 mediated m6A modification plays an oncogenic role in cutaneous squamous cell carcinoma by regulating ΔNp63. Biochemical and Biophysical Research Communications, 515(2), 310-317.
30. Zhuang, C., Zhuang, C., Luo, X., Huang, X., Yao, L., Li, J., ... & Gui, Y. (2019). N6‐methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO‐PGC‐1α signaling axis. Journal of Cellular and Molecular Medicine, 23(3), 2163-2173.