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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.


Related in: MedlinePlus

Key functional and structural amino acids are well conserved within MBD domain of MBD4. The MBD domain alignment is shown. A solution structure of the MBDs from MeCP2 and MBD1 has been determined, consisting of four anti-parallel β-strands, two of which were proposed to interact with the major groove of DNA, where a methyl group would be located. In addition, a number of conserved residues throughout the MBD domains of MeCP2 and MBD1 can be easily revealed by alignment, despite their full-length sequences sharing only moderate homology. The MBDs of MBD4, MBD1 and MeCP2 were aligned and compared to indicate essential residues within the MBD of MBD4 that are responsible for binding to methylated DNA sequences. Essential Residues are well conserved in the MBD of MBD4 [93]. In addition, amino acids within the MBD of MBD4 that are important for DNA binding found by mutational analyses and associated with Rett syndrome in MeCP2 are also well conserved. Sequence alignments of the MBD domain of MBD proteins were generated with clustalX module of Jalview software.
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f3-cancers-03-01798: Key functional and structural amino acids are well conserved within MBD domain of MBD4. The MBD domain alignment is shown. A solution structure of the MBDs from MeCP2 and MBD1 has been determined, consisting of four anti-parallel β-strands, two of which were proposed to interact with the major groove of DNA, where a methyl group would be located. In addition, a number of conserved residues throughout the MBD domains of MeCP2 and MBD1 can be easily revealed by alignment, despite their full-length sequences sharing only moderate homology. The MBDs of MBD4, MBD1 and MeCP2 were aligned and compared to indicate essential residues within the MBD of MBD4 that are responsible for binding to methylated DNA sequences. Essential Residues are well conserved in the MBD of MBD4 [93]. In addition, amino acids within the MBD of MBD4 that are important for DNA binding found by mutational analyses and associated with Rett syndrome in MeCP2 are also well conserved. Sequence alignments of the MBD domain of MBD proteins were generated with clustalX module of Jalview software.

Mentions: Mice lacking methyl-CpG binding proteins are viable during early development. With the exception of mbd4−/− mice, there is no association with activation or impaired apoptotic signaling pathways [92]. MBD4 is a methyl-CpG binding DNA protein containing a highly conserved glycosylase domain at the C-terminal [1]. It is proposed to be involved in the repair of mismatches resulting from cytosine deamination. In contrast to the poorly conserved N-terminal MBD domain, the key amino acids that are responsible for binding specificity and structure are well conserved [92,93] (Figure 2 and Figure 3.) Spontaneous hydrolytic deamination of methylated cytosine causes C•T transitions at meCpG, and non-methylated CpG mutates to UpG. MBD4 was shown to excise and repair both C•T and C•U mutations at methylated and non-methylated CpGs via its glycosylase domain and adjacent binding site (Figure 2 and Figure 3). Novel interacting partners of MBD4 include MLH1 and Fas-associated death domain (FADD) proteins, suggesting a potential link between genome surveillance and apoptosis [94,95]. Consistent with these observations, reduced apoptosis occurs in the small intestine of mbd4−/− mice in response to a variety of DNA-damaging agents, and increased tumorigenicity was observed for mbd4−/− mice on a tumor-susceptible Apc min background [40,96,97]. Recently it has been demonstrated that TDG is essential for early mouse development and the embryonic lethal phenotype includes mis-expression of developmental genes suggesting it may have a structural role in maintaining sites of active gene expression [98]. There was some evidence that TDG might also function to erase aberrant methylation at normally methylation free CpG island promoters. A bisulfite deep sequencing approach of TDG mutant embryos may address this possibility more fully, with the caveat that the sites may be 5-hydroxymethylated and not 5mC modified.


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)

Key functional and structural amino acids are well conserved within MBD domain of MBD4. The MBD domain alignment is shown. A solution structure of the MBDs from MeCP2 and MBD1 has been determined, consisting of four anti-parallel β-strands, two of which were proposed to interact with the major groove of DNA, where a methyl group would be located. In addition, a number of conserved residues throughout the MBD domains of MeCP2 and MBD1 can be easily revealed by alignment, despite their full-length sequences sharing only moderate homology. The MBDs of MBD4, MBD1 and MeCP2 were aligned and compared to indicate essential residues within the MBD of MBD4 that are responsible for binding to methylated DNA sequences. Essential Residues are well conserved in the MBD of MBD4 [93]. In addition, amino acids within the MBD of MBD4 that are important for DNA binding found by mutational analyses and associated with Rett syndrome in MeCP2 are also well conserved. Sequence alignments of the MBD domain of MBD proteins were generated with clustalX module of Jalview software.
© Copyright Policy
Related In: Results  -  Collection

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

f3-cancers-03-01798: Key functional and structural amino acids are well conserved within MBD domain of MBD4. The MBD domain alignment is shown. A solution structure of the MBDs from MeCP2 and MBD1 has been determined, consisting of four anti-parallel β-strands, two of which were proposed to interact with the major groove of DNA, where a methyl group would be located. In addition, a number of conserved residues throughout the MBD domains of MeCP2 and MBD1 can be easily revealed by alignment, despite their full-length sequences sharing only moderate homology. The MBDs of MBD4, MBD1 and MeCP2 were aligned and compared to indicate essential residues within the MBD of MBD4 that are responsible for binding to methylated DNA sequences. Essential Residues are well conserved in the MBD of MBD4 [93]. In addition, amino acids within the MBD of MBD4 that are important for DNA binding found by mutational analyses and associated with Rett syndrome in MeCP2 are also well conserved. Sequence alignments of the MBD domain of MBD proteins were generated with clustalX module of Jalview software.
Mentions: Mice lacking methyl-CpG binding proteins are viable during early development. With the exception of mbd4−/− mice, there is no association with activation or impaired apoptotic signaling pathways [92]. MBD4 is a methyl-CpG binding DNA protein containing a highly conserved glycosylase domain at the C-terminal [1]. It is proposed to be involved in the repair of mismatches resulting from cytosine deamination. In contrast to the poorly conserved N-terminal MBD domain, the key amino acids that are responsible for binding specificity and structure are well conserved [92,93] (Figure 2 and Figure 3.) Spontaneous hydrolytic deamination of methylated cytosine causes C•T transitions at meCpG, and non-methylated CpG mutates to UpG. MBD4 was shown to excise and repair both C•T and C•U mutations at methylated and non-methylated CpGs via its glycosylase domain and adjacent binding site (Figure 2 and Figure 3). Novel interacting partners of MBD4 include MLH1 and Fas-associated death domain (FADD) proteins, suggesting a potential link between genome surveillance and apoptosis [94,95]. Consistent with these observations, reduced apoptosis occurs in the small intestine of mbd4−/− mice in response to a variety of DNA-damaging agents, and increased tumorigenicity was observed for mbd4−/− mice on a tumor-susceptible Apc min background [40,96,97]. Recently it has been demonstrated that TDG is essential for early mouse development and the embryonic lethal phenotype includes mis-expression of developmental genes suggesting it may have a structural role in maintaining sites of active gene expression [98]. There was some evidence that TDG might also function to erase aberrant methylation at normally methylation free CpG island promoters. A bisulfite deep sequencing approach of TDG mutant embryos may address this possibility more fully, with the caveat that the sites may be 5-hydroxymethylated and not 5mC modified.

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.


Related in: MedlinePlus