Journal
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 83
Volume 83, Issue -, Pages 585-+Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-biochem-060713-035513
Keywords
DNA/RNA demethylation; 5-methylcytosine oxidation; Fe(II)/alpha-ketoglutarate-dependent dioxygenases; Tet; N-6-methyladenosine
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NHGRI NIH HHS [HG006827, R01 HG006827] Funding Source: Medline
- NIDDK NIH HHS [U01 DK089565, U01DK089565] Funding Source: Medline
- NIGMS NIH HHS [GM68804, R01 GM071440, GM071440, R01 GM068804] Funding Source: Medline
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG006827] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U01DK089565] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM068804, R01GM071440] Funding Source: NIH RePORTER
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The importance of eukaryotic DNA methylation [5-methylcytosine (5mC)] in transcriptional regulation and development was first suggested almost 40 years ago. However, the molecular mechanism underlying the dynamic nature of this epigenetic mark was not understood until recently, following the discovery that the TET proteins, a family of AlkB-like Fe(II)/alpha-ketoglutarate-dependent dioxygenases, can oxidize 5mC to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Since then, several mechanisms that are responsible for processing oxidized 5mC derivatives to achieve DNA demethylation have emerged. Our biochemical understanding of the DNA demethylation process has prompted new investigations into the biological functions of DNA demethylation. Characterization of two additional AlkB family proteins, FTO and ALKBH5, showed that they possess demethylase activity toward N-6-methyladenosine (m(6)A) in RNA, indicating that members of this subfamily of dioxygenases have a general function in demethylating nucleic acids. In this review, we discuss recent advances in this emerging field, focusing on the mechanism and function of TET-mediated DNA demethylation.
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