Limits...
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.


Evolutionary timeline of the two mammalian Thymine glycosylase proteins: Methyl-CpG binding domain protein 4 and Thymine-DNA glycosylase (TDG). The ortholog of proteins including the MBD domain and the glycosylase domain of human MBD4 and of full length human TDG were inferred initially by reciprocal best BLASTP searches against the non-redundant protein sequences database, and confirmed by phylogenetic reconstructions. Neighbor-joining (NJ) phylogenetic trees were constructed for domains of MBD4 and full length TDG proteins. Maximum likelihood (ML) analyses were performed using the PHYML module from Geneious pro software, following the JTT model of amino acid substitution. Protein domains were identified using InterProScan and Conserved Domains servers. Published procedures for this bioinformatic approach were followed [99]. Both glycosylase ancestors of MBD4 and TDG were found in Bacteria. Glycosylase ancestors of MBD4 were found in Archaea, whereas only a hypothetical TDG Archaea ortholog was identified. Both glycosylase ancestors of MBD4 and TDG were found in Plants and Fungi, in contrast, the earliest MBD domain ancestors were in plants and not in Fungi. TDG protein was found in almost all the species throughout evolution, the full length MBD4 though, emerges as a fusion protein only from Chordates: the representative of Invertebrate-Vertebrate transition.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3757391&req=5

f4-cancers-03-01798: Evolutionary timeline of the two mammalian Thymine glycosylase proteins: Methyl-CpG binding domain protein 4 and Thymine-DNA glycosylase (TDG). The ortholog of proteins including the MBD domain and the glycosylase domain of human MBD4 and of full length human TDG were inferred initially by reciprocal best BLASTP searches against the non-redundant protein sequences database, and confirmed by phylogenetic reconstructions. Neighbor-joining (NJ) phylogenetic trees were constructed for domains of MBD4 and full length TDG proteins. Maximum likelihood (ML) analyses were performed using the PHYML module from Geneious pro software, following the JTT model of amino acid substitution. Protein domains were identified using InterProScan and Conserved Domains servers. Published procedures for this bioinformatic approach were followed [99]. Both glycosylase ancestors of MBD4 and TDG were found in Bacteria. Glycosylase ancestors of MBD4 were found in Archaea, whereas only a hypothetical TDG Archaea ortholog was identified. Both glycosylase ancestors of MBD4 and TDG were found in Plants and Fungi, in contrast, the earliest MBD domain ancestors were in plants and not in Fungi. TDG protein was found in almost all the species throughout evolution, the full length MBD4 though, emerges as a fusion protein only from Chordates: the representative of Invertebrate-Vertebrate transition.

Mentions: Both TDG and MBD4 have been shown to be capable of removing guanine (G):uracil (U) mispair and guanine (G):thymine (T) mispair, products from deamination of the exocyclic amino group in cytosine and 5-methylcytosine. These two coexisting glycosylases seem redundant for a system targeting mismatched thymine and uracil. Their evolutionary timeline is very different (Figure 4). Both glycosylase ancestors of MBD4 and TDG were found in Bacteria, with twice as many glycosylase orthologs of MBD4 in Bacteria compared to TDG. Glycosylase ancestors of MBD4 were also found in Archaea, whereas only a hypothetical protein TDG Archaea ortholog was identified. Both glycosylase ancestors of MBD4 and TDG were identified in plants and fungi. In contrast, the earliest MBD domain ancestors exist in plants but not in fungi. Most importantly, whereas the TDG protein was found in almost all the species throughout evolution, full length MBD4 emerges as a fusion protein only from Chordates onwards - the representative of Invertebrate-Vertebrate transition. This suggest in a more complex system such as vertebrates, an additional glycosylase like MBD4 is required to maintain genome integrity and MBD4 may possess some special roles such as apoptosis signaling, where fatal mismatches cannot be repaired. Interestingly, according to the evolutionary rate, the proportion of CG sites in vertebrates is far less than that of lower organisms, due to the accumulation of evolutionary repair events of spontaneous deamination. The additional glycosylase system aiming at a lower proportion of CG sites may result in a more precise genome surveillance, which is a requirement in higher animals. It is not surprising that a defect in this system results contributes to disease pathology, for example by increasing the mutation rate at a second site in the two hits (Knudsen) cancer model.


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)

Evolutionary timeline of the two mammalian Thymine glycosylase proteins: Methyl-CpG binding domain protein 4 and Thymine-DNA glycosylase (TDG). The ortholog of proteins including the MBD domain and the glycosylase domain of human MBD4 and of full length human TDG were inferred initially by reciprocal best BLASTP searches against the non-redundant protein sequences database, and confirmed by phylogenetic reconstructions. Neighbor-joining (NJ) phylogenetic trees were constructed for domains of MBD4 and full length TDG proteins. Maximum likelihood (ML) analyses were performed using the PHYML module from Geneious pro software, following the JTT model of amino acid substitution. Protein domains were identified using InterProScan and Conserved Domains servers. Published procedures for this bioinformatic approach were followed [99]. Both glycosylase ancestors of MBD4 and TDG were found in Bacteria. Glycosylase ancestors of MBD4 were found in Archaea, whereas only a hypothetical TDG Archaea ortholog was identified. Both glycosylase ancestors of MBD4 and TDG were found in Plants and Fungi, in contrast, the earliest MBD domain ancestors were in plants and not in Fungi. TDG protein was found in almost all the species throughout evolution, the full length MBD4 though, emerges as a fusion protein only from Chordates: the representative of Invertebrate-Vertebrate transition.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757391&req=5

f4-cancers-03-01798: Evolutionary timeline of the two mammalian Thymine glycosylase proteins: Methyl-CpG binding domain protein 4 and Thymine-DNA glycosylase (TDG). The ortholog of proteins including the MBD domain and the glycosylase domain of human MBD4 and of full length human TDG were inferred initially by reciprocal best BLASTP searches against the non-redundant protein sequences database, and confirmed by phylogenetic reconstructions. Neighbor-joining (NJ) phylogenetic trees were constructed for domains of MBD4 and full length TDG proteins. Maximum likelihood (ML) analyses were performed using the PHYML module from Geneious pro software, following the JTT model of amino acid substitution. Protein domains were identified using InterProScan and Conserved Domains servers. Published procedures for this bioinformatic approach were followed [99]. Both glycosylase ancestors of MBD4 and TDG were found in Bacteria. Glycosylase ancestors of MBD4 were found in Archaea, whereas only a hypothetical TDG Archaea ortholog was identified. Both glycosylase ancestors of MBD4 and TDG were found in Plants and Fungi, in contrast, the earliest MBD domain ancestors were in plants and not in Fungi. TDG protein was found in almost all the species throughout evolution, the full length MBD4 though, emerges as a fusion protein only from Chordates: the representative of Invertebrate-Vertebrate transition.
Mentions: Both TDG and MBD4 have been shown to be capable of removing guanine (G):uracil (U) mispair and guanine (G):thymine (T) mispair, products from deamination of the exocyclic amino group in cytosine and 5-methylcytosine. These two coexisting glycosylases seem redundant for a system targeting mismatched thymine and uracil. Their evolutionary timeline is very different (Figure 4). Both glycosylase ancestors of MBD4 and TDG were found in Bacteria, with twice as many glycosylase orthologs of MBD4 in Bacteria compared to TDG. Glycosylase ancestors of MBD4 were also found in Archaea, whereas only a hypothetical protein TDG Archaea ortholog was identified. Both glycosylase ancestors of MBD4 and TDG were identified in plants and fungi. In contrast, the earliest MBD domain ancestors exist in plants but not in fungi. Most importantly, whereas the TDG protein was found in almost all the species throughout evolution, full length MBD4 emerges as a fusion protein only from Chordates onwards - the representative of Invertebrate-Vertebrate transition. This suggest in a more complex system such as vertebrates, an additional glycosylase like MBD4 is required to maintain genome integrity and MBD4 may possess some special roles such as apoptosis signaling, where fatal mismatches cannot be repaired. Interestingly, according to the evolutionary rate, the proportion of CG sites in vertebrates is far less than that of lower organisms, due to the accumulation of evolutionary repair events of spontaneous deamination. The additional glycosylase system aiming at a lower proportion of CG sites may result in a more precise genome surveillance, which is a requirement in higher animals. It is not surprising that a defect in this system results contributes to disease pathology, for example by increasing the mutation rate at a second site in the two hits (Knudsen) cancer model.

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.