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Apoptosis and DNA methylation.

Meng HX, Hackett JA, Nestor C, Dunican DS, Madej M, Reddington JP, Pennings S, Harrison DJ, Meehan RR - Cancers (Basel) (2011)

Bottom Line: Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues.The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity.This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Genetics Unit, IGMM, Western General Hospital, Edinburgh EH4 2XU, UK. richard.meehan@hgu.mrc.ac.uk.

ABSTRACT
Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG.

No MeSH data available.


Maintainance of DNA Methylation. (A-B)The preferential substrate for the maintenance cytosine methyltransferase, DNMT1, is hemi-methylated CpG sites resulting from newly synthesized DNA in somatic cells. DNMT1 is present at the replication fork, and functions with the help of partner proteins including UHRF and PCNA. (C) Post-replication, DNMT1 and a methyl-CpG binding protein MBD4 can be localized together at DNA damage sites and may be part of cellular pathway response that activates apoptosis. MBD4 interacts directly with both DNMT1 and MLH1 leading to recruitment of all three at DNA damage sites. (D) MBD4 has also been shown to recruit Fas-associated death domain protein (FADD), which bridges death receptors with initiator caspases. FADD may also be an apoptotic effector via MBD4. (E) Several active DNA demethylation models have been proposed. MBD4 was reported to execute active DNA demethylation at the CYP27B1 promoter in response to PTH (Parathyroid Hormone) signaling. Similarly TDG (Thymine DNA glycosylase) can also interact with Dnmt3A and Dnmt3B and function as 5meC glycosylase activity against hemi-methylated DNA with the same weak excision activity as MBD4. In zebrafish embryos Aid, Mbd4 and the DNA repair protein Gadd45a may cooperate to induce demethylation. Thymine glycosylases such as TDG and MBD4 may function on deamination of 5-methyl-cytosine by repairing the resulting mismatch. (F) TET1 is capable of acting on both fully methylated and hemi-methylated DNA, producing 5-hydroxymethylcytosine (5hmC) in DNA, which may also act in signaling pathways associated with turnover and maintenance of the epigenome.
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f1-cancers-03-01798: Maintainance of DNA Methylation. (A-B)The preferential substrate for the maintenance cytosine methyltransferase, DNMT1, is hemi-methylated CpG sites resulting from newly synthesized DNA in somatic cells. DNMT1 is present at the replication fork, and functions with the help of partner proteins including UHRF and PCNA. (C) Post-replication, DNMT1 and a methyl-CpG binding protein MBD4 can be localized together at DNA damage sites and may be part of cellular pathway response that activates apoptosis. MBD4 interacts directly with both DNMT1 and MLH1 leading to recruitment of all three at DNA damage sites. (D) MBD4 has also been shown to recruit Fas-associated death domain protein (FADD), which bridges death receptors with initiator caspases. FADD may also be an apoptotic effector via MBD4. (E) Several active DNA demethylation models have been proposed. MBD4 was reported to execute active DNA demethylation at the CYP27B1 promoter in response to PTH (Parathyroid Hormone) signaling. Similarly TDG (Thymine DNA glycosylase) can also interact with Dnmt3A and Dnmt3B and function as 5meC glycosylase activity against hemi-methylated DNA with the same weak excision activity as MBD4. In zebrafish embryos Aid, Mbd4 and the DNA repair protein Gadd45a may cooperate to induce demethylation. Thymine glycosylases such as TDG and MBD4 may function on deamination of 5-methyl-cytosine by repairing the resulting mismatch. (F) TET1 is capable of acting on both fully methylated and hemi-methylated DNA, producing 5-hydroxymethylcytosine (5hmC) in DNA, which may also act in signaling pathways associated with turnover and maintenance of the epigenome.

Mentions: Three methyltransferase enzymes, Dnmt1, Dnmt3a and Dnmt3b coordinate the establishment and maintenance of DNA methylation patterns in mammals (Figure 1). The ‘de novo’ methyltransferases, Dnmt3a and Dnmt3b, target cytosine methylation to previously unmethylated CpG dinucleotides, whereas the ‘maintenance’ enzyme, DNA methyltransferase-1 (Dnmt1), preserves existing methylated sites [18]. DNMT3a and 3b are thought to be de novo methylases with an equal preference for hemimethylated and unmethylated DNA, which are necessary for de novo methylation of the genome during development and potentially newly integrated retroviral sequences [19,20]. The N-terminal region interacts with many chromatin-associated proteins including the de novo methyltransferases, MeCPs and histone modifying enzymes. It also contains a nuclear localization signal, a PCNA (proliferating cell nuclear antigen)-interacting domain, a replication targeting region and a cysteine-rich Zn2+-binding domain that can potentially bind non-methylated CG rich DNA. DNMT1 also contains a domain showing homology to the polybromo-1 protein and is thought to mediate protein-protein interactions. Many of these interactions are involved in transcriptional repression [21,22]. Recent structural analysis suggests an elegant model for the maintenance DNA methylation function of Dnmt1 in which its CXXC domain specifically binds to unmethylated CpG containing DNA and resulting in a repositioning of the CXXC-BAH1 linker between the DNA and the active site of DNMT1, preventing de novo methylation [23]. Furthermore, a loop projecting from BAH2 domain interacts with the target recognition domain (TRD), stabilizing it in a retracted position, and preventing it from accessing the DNA major groove. In consequence only hemimethylated CpG dinucleotides that do not bind the CXXC domain can gain access to the active site. The multiple interactions of DNMT1 suggest that it can be a participant in multiple complex networks involved in gene regulation, epigenetic signalling and genome stability. DNMT1 is also post-translationally modified and this can modulate its protein-protein interactions, protein-DNA interactions, subcellular localization, catalytic activity and its stability [24-26]. The protein lysine methyltransferase SET7 regulates DNMT1 activity in mammalian cells by promoting degradation of DNMT1 and thus allows epigenetic changes via DNA demethylation [27]. This modification on Lysine 142 is mutually exclusive with phosphorylation on Ser143; phosphorylated DNMT1 is more stable than methylated DNMT1 [28].


Apoptosis and DNA methylation.

Meng HX, Hackett JA, Nestor C, Dunican DS, Madej M, Reddington JP, Pennings S, Harrison DJ, Meehan RR - Cancers (Basel) (2011)

Maintainance of DNA Methylation. (A-B)The preferential substrate for the maintenance cytosine methyltransferase, DNMT1, is hemi-methylated CpG sites resulting from newly synthesized DNA in somatic cells. DNMT1 is present at the replication fork, and functions with the help of partner proteins including UHRF and PCNA. (C) Post-replication, DNMT1 and a methyl-CpG binding protein MBD4 can be localized together at DNA damage sites and may be part of cellular pathway response that activates apoptosis. MBD4 interacts directly with both DNMT1 and MLH1 leading to recruitment of all three at DNA damage sites. (D) MBD4 has also been shown to recruit Fas-associated death domain protein (FADD), which bridges death receptors with initiator caspases. FADD may also be an apoptotic effector via MBD4. (E) Several active DNA demethylation models have been proposed. MBD4 was reported to execute active DNA demethylation at the CYP27B1 promoter in response to PTH (Parathyroid Hormone) signaling. Similarly TDG (Thymine DNA glycosylase) can also interact with Dnmt3A and Dnmt3B and function as 5meC glycosylase activity against hemi-methylated DNA with the same weak excision activity as MBD4. In zebrafish embryos Aid, Mbd4 and the DNA repair protein Gadd45a may cooperate to induce demethylation. Thymine glycosylases such as TDG and MBD4 may function on deamination of 5-methyl-cytosine by repairing the resulting mismatch. (F) TET1 is capable of acting on both fully methylated and hemi-methylated DNA, producing 5-hydroxymethylcytosine (5hmC) in DNA, which may also act in signaling pathways associated with turnover and maintenance of the epigenome.
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Related In: Results  -  Collection

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f1-cancers-03-01798: Maintainance of DNA Methylation. (A-B)The preferential substrate for the maintenance cytosine methyltransferase, DNMT1, is hemi-methylated CpG sites resulting from newly synthesized DNA in somatic cells. DNMT1 is present at the replication fork, and functions with the help of partner proteins including UHRF and PCNA. (C) Post-replication, DNMT1 and a methyl-CpG binding protein MBD4 can be localized together at DNA damage sites and may be part of cellular pathway response that activates apoptosis. MBD4 interacts directly with both DNMT1 and MLH1 leading to recruitment of all three at DNA damage sites. (D) MBD4 has also been shown to recruit Fas-associated death domain protein (FADD), which bridges death receptors with initiator caspases. FADD may also be an apoptotic effector via MBD4. (E) Several active DNA demethylation models have been proposed. MBD4 was reported to execute active DNA demethylation at the CYP27B1 promoter in response to PTH (Parathyroid Hormone) signaling. Similarly TDG (Thymine DNA glycosylase) can also interact with Dnmt3A and Dnmt3B and function as 5meC glycosylase activity against hemi-methylated DNA with the same weak excision activity as MBD4. In zebrafish embryos Aid, Mbd4 and the DNA repair protein Gadd45a may cooperate to induce demethylation. Thymine glycosylases such as TDG and MBD4 may function on deamination of 5-methyl-cytosine by repairing the resulting mismatch. (F) TET1 is capable of acting on both fully methylated and hemi-methylated DNA, producing 5-hydroxymethylcytosine (5hmC) in DNA, which may also act in signaling pathways associated with turnover and maintenance of the epigenome.
Mentions: Three methyltransferase enzymes, Dnmt1, Dnmt3a and Dnmt3b coordinate the establishment and maintenance of DNA methylation patterns in mammals (Figure 1). The ‘de novo’ methyltransferases, Dnmt3a and Dnmt3b, target cytosine methylation to previously unmethylated CpG dinucleotides, whereas the ‘maintenance’ enzyme, DNA methyltransferase-1 (Dnmt1), preserves existing methylated sites [18]. DNMT3a and 3b are thought to be de novo methylases with an equal preference for hemimethylated and unmethylated DNA, which are necessary for de novo methylation of the genome during development and potentially newly integrated retroviral sequences [19,20]. The N-terminal region interacts with many chromatin-associated proteins including the de novo methyltransferases, MeCPs and histone modifying enzymes. It also contains a nuclear localization signal, a PCNA (proliferating cell nuclear antigen)-interacting domain, a replication targeting region and a cysteine-rich Zn2+-binding domain that can potentially bind non-methylated CG rich DNA. DNMT1 also contains a domain showing homology to the polybromo-1 protein and is thought to mediate protein-protein interactions. Many of these interactions are involved in transcriptional repression [21,22]. Recent structural analysis suggests an elegant model for the maintenance DNA methylation function of Dnmt1 in which its CXXC domain specifically binds to unmethylated CpG containing DNA and resulting in a repositioning of the CXXC-BAH1 linker between the DNA and the active site of DNMT1, preventing de novo methylation [23]. Furthermore, a loop projecting from BAH2 domain interacts with the target recognition domain (TRD), stabilizing it in a retracted position, and preventing it from accessing the DNA major groove. In consequence only hemimethylated CpG dinucleotides that do not bind the CXXC domain can gain access to the active site. The multiple interactions of DNMT1 suggest that it can be a participant in multiple complex networks involved in gene regulation, epigenetic signalling and genome stability. DNMT1 is also post-translationally modified and this can modulate its protein-protein interactions, protein-DNA interactions, subcellular localization, catalytic activity and its stability [24-26]. The protein lysine methyltransferase SET7 regulates DNMT1 activity in mammalian cells by promoting degradation of DNMT1 and thus allows epigenetic changes via DNA demethylation [27]. This modification on Lysine 142 is mutually exclusive with phosphorylation on Ser143; phosphorylated DNMT1 is more stable than methylated DNMT1 [28].

Bottom Line: Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues.The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity.This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Genetics Unit, IGMM, Western General Hospital, Edinburgh EH4 2XU, UK. richard.meehan@hgu.mrc.ac.uk.

ABSTRACT
Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG.

No MeSH data available.