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Cellular and Molecular Life Sciences (2018) 75:1339–1348
https://doi.org/10.1007/s00018-017-2721-8
REVIEW
The TET enzymes
Peppi Koivunen
1
· Tuomas Laukka
1
Received: 31 August 2017 / Revised: 23 November 2017 / Accepted: 24 November 2017 / Published online: 28 November 2017
© Springer International Publishing AG, part of Springer Nature 2017
Abstract
During the past decade, we have learnt that the most common DNA modification, 5-methylcytosine (5mC), playing crucial
roles in development and disease, is not stable but can be actively reversed to its unmodified form via enzymatic catalysis
involving the TET enzymes. These ground-breaking discoveries have been achieved thanks to technological advances in the
detection of the oxidized forms of 5mC and to the boldness of individual scientists. The TET enzymes require molecular
oxygen for their catalysis, making them important targets for hypoxia research. They also require special cofactors which
enable additional levels of regulation. Moreover, mutations and other genetic alterations in TETs are found, especially in
myeloid malignances. This review focuses on the kinetic and inhibitory properties of the TET enzymes and the role of TETs
in cellular differentiation and transformation and in cancer.
Keywords Cancer · DNA methylation · EMT · Gene regulation · 5hmC · Hypoxia
Introduction
The enzyme family of 2-oxoglutarate-dependent dioxyge-
nases (2-OGDDs) gained a new family member in 2009
when the conversion of 5mC to 5-hydroxymethyl cytosine
(5hmC) in DNA was found to be associated with catalysis
by TET1 [1]. TET1 in 10q22 had actually been cloned a
few years earlier as a leukemia-associated protein with a
CXXC domain (LCX) as a fusion partner of mixed-lineage
leukemia (MLL) in 11q23, and was suggested as playing a
role in the pathogenesis of 11q23-associated leukemia [2].
The first acute myeloid leukemia (AML) patient with this
TET1 translocation was subsequently characterized and the
name Ten-Eleven Translocation was suggested [3]. Based
on sequence homology, the existence of three isoenzymes
in human and mouse was recognized, although no function
could yet be associated with these proteins [3]. An attempt
to identify mammalian enzymes that would modify 5mC
by means of structurally informed iterative sequence pro-
file searches using the oxygenase domains of Trypanosomal
JBP1 and JBP2, which are 2-OGDDs and catalyze the first
step in β-
d
-glucosyl hydroxymethyluracil (base J) synthesis,
revealed homology with the TETs [1]. Further experimental
data then showed that TET1 overexpression resulted in a
reduction in 5mC levels in genomic DNA and the appear-
ance of a novel species, identified as 5hmC [1]. Human
embryonic stem cells (ES) and Purkinje cells were the first
cell types reported to contain 5hmC [1, 4]. Subsequently two
isoenzymes, TET2 and TET3, were shown to possess similar
catalytic activity [5].
The 2-OGDD family has ~ 70 members in mammals. The
others in addition to the TETs are, for example, numerous
histone lysine demethylases (KDMs), the prolyl 4-hydroxy-
lases that modify the hypoxia-inducible factor (HIF-P4Hs)
or collagens (collagen P4Hs), the hypoxia-inducible factor
asparagine hydroxylase FIH and the obesity-associated FTO,
the first identified RNA demethylase (for a complete list see
[6]). The 2-OGDDs share the same reaction mechanism and
cofactors, but their substrates vary from DNA to RNA, pro-
teins and fatty acids. 2-OGDDs require Fe
2+
, 2-oxoglutar-
ate (2-OG/α-ketoglutarate), molecular oxygen [6] and many
require a reducing agent, typically vitamin C (ascorbate) to
support the reaction [6, 7]. The cofactors are coordinated at
the active site by conserved residues, iron by two histidines
and an aspartate and 2-oxoglutarate by a positively charged
residue, an arginine or a lysine. In TETs this latter is an
arginine. The catalytic domains possess a double-stranded
β-helix (DSBH) structure known as a jelly roll. Following
Cellular andMolecular Life Sciences
* Peppi Koivunen
peppi.koivunen@oulu.fi
1
Faculty of Biochemistry and Molecular Medicine, Biocenter
Oulu, Oulu Center for Cell-Matrix Research, University
of Oulu, 90014 Oulu, Finland
@Phil_Robichaud
@deepthiw
@JoseServera