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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 description of inactivating mutations in TET2 suggests that cellular transformation is in part caused by the deregulation of this 5-mC conversion.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

Regulation of DNA methylation and demethylation. DNA demethylation can occur spontaneously via the DNMT enzymes that methylated the nucleotide cytosine (5-methylcytosine, 5-mC) originally. A passive replication-dependent mechanism of DNA methylation is also possible. Several active demethylation pathways have been postulated. TET family proteins catalyze the oxidation of 5-mC into 5-hydroxymethylcytosine (5-hmC) and can further oxidize 5-hmC to 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC). 5-hmC recognition and transformation into 5-hydroxymethyluracyl (5-hmU) by activation-induced deaminase (AID) to facilitate repair by DNA glycosylase and the base-excision repair (BER) pathway is still controversial. These latter activities are also thought to process 5-fC and 5-caC into unmodified cytosine . The decarboxylases involved in this process are still to be identified. APOBEC, apolipoprotein B mRNA editing enzyme; DNMT, DNA methyltransferase; T, thymine; TDG, thymine DNA glycosylase; TET, ten-eleven translocation.
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Fig1: Regulation of DNA methylation and demethylation. DNA demethylation can occur spontaneously via the DNMT enzymes that methylated the nucleotide cytosine (5-methylcytosine, 5-mC) originally. A passive replication-dependent mechanism of DNA methylation is also possible. Several active demethylation pathways have been postulated. TET family proteins catalyze the oxidation of 5-mC into 5-hydroxymethylcytosine (5-hmC) and can further oxidize 5-hmC to 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC). 5-hmC recognition and transformation into 5-hydroxymethyluracyl (5-hmU) by activation-induced deaminase (AID) to facilitate repair by DNA glycosylase and the base-excision repair (BER) pathway is still controversial. These latter activities are also thought to process 5-fC and 5-caC into unmodified cytosine . The decarboxylases involved in this process are still to be identified. APOBEC, apolipoprotein B mRNA editing enzyme; DNMT, DNA methyltransferase; T, thymine; TDG, thymine DNA glycosylase; TET, ten-eleven translocation.

Mentions: Although DNA methylation has long been recognized, and cytosine methylation by DNMT3A and DNMT3B has been shown to be reversible in vitro [9], the mechanism of DNA demethylation was unclear until the functional analyses of the TET family proteins [1,2]. Due to its poor recognition of 5-hmC, which results from TET activity, DNMT1 is not able to perform the methylation of the neo-synthetized DNA strand (maintenance methylation). So the methylation information is lost in dividing cells, in a so-called passive manner (Figure 1). The three enzymes of the TET family (TET1, TET2 and TET3) are able to further oxidize 5-hmC into 5-formylcytosine (5-fC) and then 5-carboxycytosine (5-caC) [10,11]. Thymidine DNA glycosylase (TDG) is then able to remove 5-fC and 5-caC, triggering base-excision repair (BER) activity and the reintroduction of unmethylated cytosine [11-13]. The existence of decarboxylases that convert 5-caC to unmethylated cytosine is hypothetical. It has been suggested that the deamination of 5-hmC into 5-hydroxymethyluracil (5-hmU) occurs via activation-induced deaminase (AID) and apolipoprotein B mRNA editing enzyme (APOBEC), followed by TDG and BER mechanisms [14]. However, this remains controversial because 5-hmU residues may also originate from TET-mediated oxidation of thymine [15]. In addition, the activity of recombinant AID decreases with the size of the cytosine C5 electron cloud and does not show any activity on 5-hmC in vitro [16,17]. Indeed, AID exhibits its strongest activity against unmodified cytosine. Thymine resulting from deamination of 5-mC is not easily recognized by DNA repair machinery and is considered mutagenic. These branches of the cycle need to be further investigated in a cell- and tissue-dependent context. Regardless, TET proteins as well as several other proteins (Table 1) are essential players in the demethylation of 5-mC.Figure 1


TET proteins and the control of cytosine demethylation in cancer.

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

Regulation of DNA methylation and demethylation. DNA demethylation can occur spontaneously via the DNMT enzymes that methylated the nucleotide cytosine (5-methylcytosine, 5-mC) originally. A passive replication-dependent mechanism of DNA methylation is also possible. Several active demethylation pathways have been postulated. TET family proteins catalyze the oxidation of 5-mC into 5-hydroxymethylcytosine (5-hmC) and can further oxidize 5-hmC to 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC). 5-hmC recognition and transformation into 5-hydroxymethyluracyl (5-hmU) by activation-induced deaminase (AID) to facilitate repair by DNA glycosylase and the base-excision repair (BER) pathway is still controversial. These latter activities are also thought to process 5-fC and 5-caC into unmodified cytosine . The decarboxylases involved in this process are still to be identified. APOBEC, apolipoprotein B mRNA editing enzyme; DNMT, DNA methyltransferase; T, thymine; TDG, thymine DNA glycosylase; 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

Fig1: Regulation of DNA methylation and demethylation. DNA demethylation can occur spontaneously via the DNMT enzymes that methylated the nucleotide cytosine (5-methylcytosine, 5-mC) originally. A passive replication-dependent mechanism of DNA methylation is also possible. Several active demethylation pathways have been postulated. TET family proteins catalyze the oxidation of 5-mC into 5-hydroxymethylcytosine (5-hmC) and can further oxidize 5-hmC to 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC). 5-hmC recognition and transformation into 5-hydroxymethyluracyl (5-hmU) by activation-induced deaminase (AID) to facilitate repair by DNA glycosylase and the base-excision repair (BER) pathway is still controversial. These latter activities are also thought to process 5-fC and 5-caC into unmodified cytosine . The decarboxylases involved in this process are still to be identified. APOBEC, apolipoprotein B mRNA editing enzyme; DNMT, DNA methyltransferase; T, thymine; TDG, thymine DNA glycosylase; TET, ten-eleven translocation.
Mentions: Although DNA methylation has long been recognized, and cytosine methylation by DNMT3A and DNMT3B has been shown to be reversible in vitro [9], the mechanism of DNA demethylation was unclear until the functional analyses of the TET family proteins [1,2]. Due to its poor recognition of 5-hmC, which results from TET activity, DNMT1 is not able to perform the methylation of the neo-synthetized DNA strand (maintenance methylation). So the methylation information is lost in dividing cells, in a so-called passive manner (Figure 1). The three enzymes of the TET family (TET1, TET2 and TET3) are able to further oxidize 5-hmC into 5-formylcytosine (5-fC) and then 5-carboxycytosine (5-caC) [10,11]. Thymidine DNA glycosylase (TDG) is then able to remove 5-fC and 5-caC, triggering base-excision repair (BER) activity and the reintroduction of unmethylated cytosine [11-13]. The existence of decarboxylases that convert 5-caC to unmethylated cytosine is hypothetical. It has been suggested that the deamination of 5-hmC into 5-hydroxymethyluracil (5-hmU) occurs via activation-induced deaminase (AID) and apolipoprotein B mRNA editing enzyme (APOBEC), followed by TDG and BER mechanisms [14]. However, this remains controversial because 5-hmU residues may also originate from TET-mediated oxidation of thymine [15]. In addition, the activity of recombinant AID decreases with the size of the cytosine C5 electron cloud and does not show any activity on 5-hmC in vitro [16,17]. Indeed, AID exhibits its strongest activity against unmodified cytosine. Thymine resulting from deamination of 5-mC is not easily recognized by DNA repair machinery and is considered mutagenic. These branches of the cycle need to be further investigated in a cell- and tissue-dependent context. Regardless, TET proteins as well as several other proteins (Table 1) are essential players in the demethylation of 5-mC.Figure 1

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 description of inactivating mutations in TET2 suggests that cellular transformation is in part caused by the deregulation of this 5-mC conversion.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