Limits...
TET proteins and the control of cytosine demethylation in cancer.

Scourzic L, Mouly E, Bernard OA - Genome Med (2015)

Bottom Line: The discovery that ten-eleven translocation (TET) proteins are α-ketoglutarate-dependent dioxygenases involved in the conversion of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine and 5-carboxycytosine has revealed new pathways in the cytosine methylation and demethylation process.The direct and indirect deregulation of methylation control through mutations in DNA methyltransferase and isocitrate dehydrogenase (IDH) genes, respectively, along with the importance of cytosine methylation in the control of normal and malignant cellular differentiation have provided a conceptual framework for understanding the early steps in cancer development.Here, we review recent advances in our understanding of the cytosine methylation cycle and its implication in cellular transformation, with an emphasis on TET enzymes and 5-hmC.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1170, équipe labellisée Ligue Contre le Cancer, 94805 Villejuif, France ; Institut Gustave Roussy, 94805 Villejuif, France ; University Paris 11 Sud, 91405 Orsay, France.

ABSTRACT
The discovery that ten-eleven translocation (TET) proteins are α-ketoglutarate-dependent dioxygenases involved in the conversion of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine and 5-carboxycytosine has revealed new pathways in the cytosine methylation and demethylation process. The description of inactivating mutations in TET2 suggests that cellular transformation is in part caused by the deregulation of this 5-mC conversion. The direct and indirect deregulation of methylation control through mutations in DNA methyltransferase and isocitrate dehydrogenase (IDH) genes, respectively, along with the importance of cytosine methylation in the control of normal and malignant cellular differentiation have provided a conceptual framework for understanding the early steps in cancer development. Here, we review recent advances in our understanding of the cytosine methylation cycle and its implication in cellular transformation, with an emphasis on TET enzymes and 5-hmC. Ongoing clinical trials targeting the activity of mutated IDH enzymes provide a proof of principle that DNA methylation is targetable, and will trigger further therapeutic applications aimed at controlling both early and late stages of cancer development.

No MeSH data available.


Related in: MedlinePlus

Primary structure and function of human TET proteins. All TET proteins present a double-stranded β helix (DSBH), a cysteine-rich domain, and one 2-oxoglutarate and three iron (II) binding sites in the carboxyl terminus, which constitute their dioxygenase catalytic domain. An amino-terminal CXXC zinc finger domain is only identified in TET1 and TET3, allowing these enzymes to bind DNA directly to CpG. Recently, the CXXC4 gene (also named inhibition of the Dvl and Axin complex, IDAX), located upstream of TET2 on chromosome 4, has been reported to tether TET2 to DNA through a physical interaction [65]. AA, amino acid; TET, ten-eleven translocation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4308928&req=5

Fig2: Primary structure and function of human TET proteins. All TET proteins present a double-stranded β helix (DSBH), a cysteine-rich domain, and one 2-oxoglutarate and three iron (II) binding sites in the carboxyl terminus, which constitute their dioxygenase catalytic domain. An amino-terminal CXXC zinc finger domain is only identified in TET1 and TET3, allowing these enzymes to bind DNA directly to CpG. Recently, the CXXC4 gene (also named inhibition of the Dvl and Axin complex, IDAX), located upstream of TET2 on chromosome 4, has been reported to tether TET2 to DNA through a physical interaction [65]. AA, amino acid; TET, ten-eleven translocation.

Mentions: TET1 was first identified as a rare fusion partner of the mixed lineage leukemia gene, resulting from the chromosomal translocation t(10;11)(q22;23) in acute leukemia [2,54-57]. The difference between TET proteins relies on their structure (Figure 2) but also on their distinct expression patterns: TET2 is more highly expressed in the hematopoietic system than TET3 and TET1. It is currently thought that the common and main function of TET proteins is to establish or maintain protective boundaries to prevent unwanted methylation of non-methylated regions [58]. Each TET protein may also have specific functions: for example, TET1 oxidizes 5-mC to 5-hmC, and TET2 and TET3 stimulate the removal of 5-hmC [59]. In ES cells, TET2 may preferentially act on gene bodies, and TET1 at promoters [60]. The role of TET-mediated cytosine oxidation at distal enhancers is currently being thoroughly investigated. Super enhancers (enhancer clusters) that produce enhancer-transcribed RNAs in mouse ES cells have recently been associated with H3K27ac, TET1 and a decrease in DNA methylation level at pluripotency-dedicated loci [61]. Also, a specific role for TET2 in the control of enhancer activity has been suggested in the context of murine ES cell differentiation [62]. This mechanism remains to be investigated in the context of cancer, and more specifically in hematological disorders.Figure 2


TET proteins and the control of cytosine demethylation in cancer.

Scourzic L, Mouly E, Bernard OA - Genome Med (2015)

Primary structure and function of human TET proteins. All TET proteins present a double-stranded β helix (DSBH), a cysteine-rich domain, and one 2-oxoglutarate and three iron (II) binding sites in the carboxyl terminus, which constitute their dioxygenase catalytic domain. An amino-terminal CXXC zinc finger domain is only identified in TET1 and TET3, allowing these enzymes to bind DNA directly to CpG. Recently, the CXXC4 gene (also named inhibition of the Dvl and Axin complex, IDAX), located upstream of TET2 on chromosome 4, has been reported to tether TET2 to DNA through a physical interaction [65]. AA, amino acid; TET, ten-eleven translocation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308928&req=5

Fig2: Primary structure and function of human TET proteins. All TET proteins present a double-stranded β helix (DSBH), a cysteine-rich domain, and one 2-oxoglutarate and three iron (II) binding sites in the carboxyl terminus, which constitute their dioxygenase catalytic domain. An amino-terminal CXXC zinc finger domain is only identified in TET1 and TET3, allowing these enzymes to bind DNA directly to CpG. Recently, the CXXC4 gene (also named inhibition of the Dvl and Axin complex, IDAX), located upstream of TET2 on chromosome 4, has been reported to tether TET2 to DNA through a physical interaction [65]. AA, amino acid; TET, ten-eleven translocation.
Mentions: TET1 was first identified as a rare fusion partner of the mixed lineage leukemia gene, resulting from the chromosomal translocation t(10;11)(q22;23) in acute leukemia [2,54-57]. The difference between TET proteins relies on their structure (Figure 2) but also on their distinct expression patterns: TET2 is more highly expressed in the hematopoietic system than TET3 and TET1. It is currently thought that the common and main function of TET proteins is to establish or maintain protective boundaries to prevent unwanted methylation of non-methylated regions [58]. Each TET protein may also have specific functions: for example, TET1 oxidizes 5-mC to 5-hmC, and TET2 and TET3 stimulate the removal of 5-hmC [59]. In ES cells, TET2 may preferentially act on gene bodies, and TET1 at promoters [60]. The role of TET-mediated cytosine oxidation at distal enhancers is currently being thoroughly investigated. Super enhancers (enhancer clusters) that produce enhancer-transcribed RNAs in mouse ES cells have recently been associated with H3K27ac, TET1 and a decrease in DNA methylation level at pluripotency-dedicated loci [61]. Also, a specific role for TET2 in the control of enhancer activity has been suggested in the context of murine ES cell differentiation [62]. This mechanism remains to be investigated in the context of cancer, and more specifically in hematological disorders.Figure 2

Bottom Line: The discovery that ten-eleven translocation (TET) proteins are α-ketoglutarate-dependent dioxygenases involved in the conversion of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine and 5-carboxycytosine has revealed new pathways in the cytosine methylation and demethylation process.The direct and indirect deregulation of methylation control through mutations in DNA methyltransferase and isocitrate dehydrogenase (IDH) genes, respectively, along with the importance of cytosine methylation in the control of normal and malignant cellular differentiation have provided a conceptual framework for understanding the early steps in cancer development.Here, we review recent advances in our understanding of the cytosine methylation cycle and its implication in cellular transformation, with an emphasis on TET enzymes and 5-hmC.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1170, équipe labellisée Ligue Contre le Cancer, 94805 Villejuif, France ; Institut Gustave Roussy, 94805 Villejuif, France ; University Paris 11 Sud, 91405 Orsay, France.

ABSTRACT
The discovery that ten-eleven translocation (TET) proteins are α-ketoglutarate-dependent dioxygenases involved in the conversion of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine and 5-carboxycytosine has revealed new pathways in the cytosine methylation and demethylation process. The description of inactivating mutations in TET2 suggests that cellular transformation is in part caused by the deregulation of this 5-mC conversion. The direct and indirect deregulation of methylation control through mutations in DNA methyltransferase and isocitrate dehydrogenase (IDH) genes, respectively, along with the importance of cytosine methylation in the control of normal and malignant cellular differentiation have provided a conceptual framework for understanding the early steps in cancer development. Here, we review recent advances in our understanding of the cytosine methylation cycle and its implication in cellular transformation, with an emphasis on TET enzymes and 5-hmC. Ongoing clinical trials targeting the activity of mutated IDH enzymes provide a proof of principle that DNA methylation is targetable, and will trigger further therapeutic applications aimed at controlling both early and late stages of cancer development.

No MeSH data available.


Related in: MedlinePlus