Volume 24, No 8, Aug 2014

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 24 Issue 8, August 2014: 1017-1020

LETTERS TO THE EDITOR

TET-catalyzed 5-methylcytosine hydroxylation is dynamically regulated by metabolites

Hui Yang¹, Huaipeng Lin¹, Haiyan Xu², Lei Zhang³, Lu Cheng⁴, Bo Wen⁴, Jianyong Shou², Kunliang Guan^1,5, Yue Xiong^1,6 and Dan Ye¹

¹Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China
²China Novartis Institutes for BioMedical Research, Shanghai, China
³Department of Chemistry, Institute of Stem Cell Research and Regenerative Medicine, Fudan University, Shanghai 200032, China
⁴Department of Biochemistry and Molecular Biology, Institute of Stem Cell Research and Regenerative Medicine, Fudan University, Shanghai 200032, China
⁵Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA
⁶Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, North Carolina 27599, USA Correspondence: Dan Ye,(yedan@fudan.edu.cn)

DNA methylation suppresses gene expression and plays a broad and important role in diverse biological processes such as development and tumor suppression1,2. DNA methylation is generally thought to be relatively stable and heritable. This view is recently changed by the discovery of TET (ten-eleven translocation) family of dioxygenases which catalyze three sequential oxidation reactions: converting 5mC first to 5hmC, and then 5-formylcytosine (5fC), and finally 5-carboxylcytosine (5caC)3,4,5,6,7. A subsequent decarboxylation of 5caC could then lead to DNA demethylation3. While the biological function and catalytic mechanism of TET enzymes are being extensively investigated, much less is currently known about their regulation. TET proteins are the members of Fe(II)/α-ketoglutarate (α-KG)-dependent dioxygenases, which require Fe(II) as a metal cofactor and α-KG as a co-substrate8,9. In various types of tumors, pathological accumulation of three metabolites, 2-HG, succinate and fumurate, that share structural similarity with α-KG, results in a competitive inhibition of α-KG-dependent TET activity, leading to a hypermethylation phenotype10,11. α-KG is produced and consumed mainly by four different metabolic pathways: as a key intermediate in the TCA cycle for energy metabolism, as an entry point for several 5-carbon amino acids to enter the TCA cycle (anaplerosis) after being converted into glutamate, being reduced back to isocitrate and then citrate for the eventual synthesis of acetyl-CoA, and being used as a co-substrate for multiple α-KG-dependent dioxygenases. These features of α-KG led us to investigate how a change in energy metabolism may influence TET activity in vivo.

10.1038/cr.2014.81

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