Nükleobazların Demetilasyonu ve Güncel Gelişmeler

Yıl 2021, Cilt: 30 Sayı: 3, 158 - 165, 30.09.2021

Kezban Kartlaşmış , Nurten Dikmen

https://doi.org/10.17827/aktd.906243

Öz

DNA dizisi aynı kalarak DNA, RNA ve proteinlerin işlev ve düzenleme mekanizmalarının etkilenmesi ile sonuçlanan gen işlevlerindeki değişiklikler epigenetik olarak tanımlanır. Son yıllarda gelişen teknolojiyle birlikte epigenetik alanında yapılan çalışmalar, insanlar üzerindeki önemli etkilerinin keşfedilmesini ve hastalıklarla ilişkisinin anlaşılmasını sağlamıştır. Birçok hastalık, epigenetik mekanizmaların düzenlenmesindeki hata ya da düzensizlik ile genlerin ifadesinin aşırı artması/baskılanması sonucunda ortaya çıkmaktadır. Son dönemlerde üzerinde çok çalışılan ve hakkında en çok bilgi sahibi olunan epigenetik mekanizmalar DNA ve RNA metilasyonudur. Epigenetik hastalık mekanizmalarının anlaşılma ve değerlendirilmesinde metilasyonların yanı sıra DNA ve RNA demetilasyon süreçleriyle ilgili olarak yapılan moleküler düzeydeki araştırmalar da büyük önem kazanmıştır.

Anahtar Kelimeler

Demetilasyon, Epigenezis, Nucleobase

Demethylation of Nucleobases and Current Developments

Öz

They defined epigenetics as changes in gene function that do not change the DNA sequence, but result in changes in the functions and regulation mechanisms of DNA, proteins and RNAs. Studies conducted in the field of epigenetics with the developing technology in recent years have enabled us to discover its important effects on humans and to understand its relationship with diseases. Many diseases occur as a result of excessive increase / suppression of the expression of genes by error or irregularity in the regulation of epigenetic mechanisms. The epigenetic mechanism that has been studied a lot and the most known epigenetic mechanism is DNA and RNA methylation. In addition to methylations, molecular-level research on DNA and RNA demethylation processes has gained great importance in understanding and evaluating epigenetic disease mechanisms.

Anahtar Kelimeler

Demethylation, epigenesis, nucleobases

Kaynakça

• 1. Gürel Ç, Nursal AF, Yiğit S. Epigenetik ve kanser. Türkiye Klinikleri J Radiat Oncol-Special Topics 2016;2:45-51.
• 2. Kaellin WG, Mcknight S. Influence of metabolism on epigenetics and disease. Cell Journal 2013;153:56-69.
• 3. Cheng Z, Zheng L, Almeida FA. Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond. J Nutr Biochem. 2018;54:1-10.
• 4. İzmirli M, Tufan T, Alptekin D. DNA Metilasyonu. Arşiv Kaynak Tarama Dergisi. 2012;21:274-282.
• 5. Traube FR, Carell T. The chemistries and consequences of DNA and RNA methylation and demethylation. RNA Biol. 2017;14:1099-1107. 6. Shen L, Song CX, He C, Zhang Y. Mechanism and function of oxidative reversal of DNA and RNA methylation. Annu Rev Biochem. 2014;83:585-614.
• 7. Jabgunde AM, Jaziri F, Bande O, Froeyen M, Abramov M, Nguyen H et al. Methylated Nucleobases: Synthesis and evaluation for base pairing in vitro and in vivo. Chemistry A European Journal. 2018;24:12695-12707.
• 8. Moulay S. N-Methylation of Nitrogen-containing organic substrates:a comprehensive overview. Current Organic Chemistry. 2019;23:1695-1937.
• 9. Bencini A, Bianchi A, Giorgi C, Paoletti P, Valtancoli B, Fusi V et al. effect of nitrogen methylation on cation and anion coordination by hexa- and heptaazamacrocycles. catalytic properties of these ligands in ATP dephosphorylation. Inorganic Chemistry. 1996;35:1114–1120.
• 10. Swift LH, Golsteyn RM. Genotoxic anti-cancer agents and their relationship to dna damage, mitosis, and checkpoint adaptation in proliferating cancer cells. Int J Mol Sci. 2014;15:3403–3431.
• 11. Auclair G, Weber M. Mechanisms of DNA methylation and demethylation in mammals. Biochimie. 2012;94:2202-2211.
• 12. Rydberg B, Lindahl T. Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-l-methionine is a potentially mutagenic reaction. EMBO Journal. 1982;1:211-216.
• 13. Zhouab Y, Konge Y, Fanf W, Tao T, Xiaog Q, Li N et al. Principles of RNA methylation and their implications for biology and medicine. Biomedicine & Pharmacotherapy J. 2020;131:1-22.
• 14. Yan F, Fujimori DG. RNA methylation by Radical SAM enzymes RlmN and Cfr proceeds via methylene transfer and hydride shift. PNAS J. 2011;108:3930-3934.
• 15. Shen H, Lan Y, Zhao Y, Shi Y, Jin J, Xie W. The emerging roles of N6-methyladenosine RNA methylation in human cancers. Biomarker Research. 2020;24:8.
• 16. Golovina AY, Sergiev PV, Dontsova OA. Methods for modified nucleotide identification in ribosomal RNA. Moscow University Chemistry Bulletin. 2012;67:82-87.
• 17. Liu W, Anyszka MJ, Piecyk K, Dickson L, Wallace A, Niedzwiecka A et al. Structural basis for nematode eIF4E binding an m2,2,7G-Cap and its implications for translation initiation. Nucleic Acids Res. 2011;39:8820–8832.
• 18. Micura R, Pils W, Höbartner C, Grubmayr K, Ebert MO, Jaun B. Methylation of the nucleobases in RNA oligonucleotides mediates duplex–hairpin conversion. Nucleic Acids Res. 2001;29:3997–4005.
• 19. Niu Y, Zhao X, Wu YS, Li MM, Wang XJ, Yang YG. N6-methyl-adenosine (m6A) in RNA: An Old Modification with A Novel Epigenetic Function. Genomics, Proteomics & Bioinformatics. 2013;11:8-17.
• 20. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology Journal. 2013;38:23–38.
• 21. Kumar S, Chinnusamy V, Mohapatra T. Epigenetics of modified DNA bases: 5-methylcytosine and beyond. Front. Genet. 2018;9:640.
• 22. Zou S, Toh JD, Wong KH, Gao YG, Hong W, Woon E. N6-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5. Scientific Reports. doi.org/10.1038/srep25677.
• 23. Neri F, Rapelli S, Krepelova A, Incarnato D, Parlato C, Basile G et al. Intragenic DNA methylation prevents spurious transcription initiation. Nature. 2017;543:72-77.
• 24. Mitra S. MGMT: a personal perspective. DNA Repair (Amst). 2007;8:1064–1070.
• 25. Xiong J, Ye TT, Ma CJ, Cheng QY, Yuan BF, Feng YQ. N6-Hydroxymethyladenine: a hydroxylation derivative of N6-methyladenine in genomic DNA of mammals. Nucleic Acids Research. 2019;47:1268–1277.
• 26. Settles S, Wang RW, Fronza G, Gold B. Effect of N3-methyladenine and an isosteric stable analogue on DNA polymerization. Journal of Nucleic acids. 2010. Article ID 426505.
• 27. Hahn MA, Szabó PE, Pfeifer GP. 5-Hydroxymethylcytosine: A stable or transient DNA modification? Genomics. 2014;104:314-323.
• 28. Hausinger RP. FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes. Crit Rev Biochem Mol Biol. 2004;39:21-68.
• 29. Guengerich FP. Introduction: Metals in Biology: α-ketoglutarate/ıron-dependent dioxygenases. Journal of Biological Chemistry. 2015;290:20700-20701.
• 30. Xu B, Liu D, Wang Z,Tian R, Zuo Y. Multi-substrate selectivity based on key loops and non-homologous domains: new insight into ALKBH family. Cellular and Molecular Life Sciences. 2021;78:129–141.
• 31. Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016;30:733–750.
• 32. Ougland R, Rognes T, Klungland A, Larsen E. Non-homologous functions of the AlkB homologs. J Mol Cell Biol. 2015;7:494-504.
• 33. Yang J, Bashkenova N, Zang R, Huang X, Wang J. The roles of TET family proteins in development and stem cells. Development. 2020. doi: 10.1242/dev.183129