User:CER20G/Hydroxymethylation

Hydroxymethylation in demethylation[edit] edit

5-Methylcytosine is a common epigenetic marker. The methyl group is modified by oxidation of the methyl group in a process called hydroxymethylation:

RCH₃ + O → RCH₂OH

This oxidation is thought to be a prelude to removal, regenerating cytosine.

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Hydroxymethylation in DNA Demethylation edit

5-methylcytosine (5mC), a common and highly stable epigenetic marker which mediates long-term gene silencing, can be converted to 5-hydroxymethylcytosine (5hmC) via enzymatic oxidation^[1].

RCH₃ + O → RCH₂OH

In mammals this enzymatic oxidation occurs via a family of enzymes known as TET (ten eleven translocation) methylcytosine dioxygenases; of which, there are three variants: TET1, TET2, & TET3^[2]. TET enzymes can further oxidize 5hmC to form formylcytosine (5fC) and carboxylcytosine (5caC)^[3]. Recognition of 5caC and 5fC by thymine-DNA glycosylase (TDG) coupled with the base-excision repair (BER) pathway results in excision of the oxidized variant which is replaced by an unmethylated cytosine^[1].

Demethylation of 5-Methylcytosine (5mC) in DNA. 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases (TET1, TET2, TET3) to generate 5-hydroxymethylcytosine (5hmC). In successive steps TET enzymes further oxidize 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and excises the glycosidic bond resulting in an apyrimidinic site (AP site). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA Glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt).^[2]

References edit

^ ^a ^b Bochtler, Matthias; Kolano, Agnieszka; Xu, Guo-Liang (2017-01). "DNA demethylation pathways: Additional players and regulators". BioEssays. 39 (1): e201600178. doi:10.1002/bies.201600178. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b Bayraktar, Gonca; Kreutz, Michael R. (2018-05-23). "The Role of Activity-Dependent DNA Demethylation in the Adult Brain and in Neurological Disorders". Frontiers in Molecular Neuroscience. 11: 169. doi:10.3389/fnmol.2018.00169. ISSN 1662-5099. PMC 5975432. PMID 29875631.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Tahiliani, Mamta; Koh, Kian Peng; Shen, Yinghua; Pastor, William A.; Bandukwala, Hozefa; Brudno, Yevgeny; Agarwal, Suneet; Iyer, Lakshminarayan M.; Liu, David R.; Aravind, L.; Rao, Anjana (2009-05-15). "Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1". Science. 324 (5929): 930–935. doi:10.1126/science.1170116. PMC 2715015. PMID 19372391.{{cite journal}}: CS1 maint: PMC format (link)

[:0-1] Bochtler, Matthias; Kolano, Agnieszka; Xu, Guo-Liang (2017-01). "DNA demethylation pathways: Additional players and regulators". BioEssays. 39 (1): e201600178. doi:10.1002/bies.201600178. {{cite journal}}: Check date values in: |date= (help)

[:1-2] Bayraktar, Gonca; Kreutz, Michael R. (2018-05-23). "The Role of Activity-Dependent DNA Demethylation in the Adult Brain and in Neurological Disorders". Frontiers in Molecular Neuroscience. 11: 169. doi:10.3389/fnmol.2018.00169. ISSN 1662-5099. PMC 5975432. PMID 29875631.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[3] Tahiliani, Mamta; Koh, Kian Peng; Shen, Yinghua; Pastor, William A.; Bandukwala, Hozefa; Brudno, Yevgeny; Agarwal, Suneet; Iyer, Lakshminarayan M.; Liu, David R.; Aravind, L.; Rao, Anjana (2009-05-15). "Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1". Science. 324 (5929): 930–935. doi:10.1126/science.1170116. PMC 2715015. PMID 19372391.{{cite journal}}: CS1 maint: PMC format (link)

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