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DNA methylation, its mediators and genome integrity.

Meng H, Cao Y, Qin J, Song X, Zhang Q, Shi Y, Cao L - Int. J. Biol. Sci. (2015)

Bottom Line: DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability.DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins.Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: 1. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China; ; 2. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China.

ABSTRACT
DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability. DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins. Multiple forms of DNA methylation are recognised by methyl-CpG binding proteins (MeCPs), which play vital roles in chromatin-based transcriptional regulation, DNA repair and replication. Accordingly, defects in DNA methylation and its mediators may cause silencing of tumour suppressor genes and misregulation of multiple cell cycles, DNA repair and chromosome stability genes, and hence contribute to genome instability in various human diseases, including cancer. Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.

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Mediators of DNA methylation machinery. (A) Domain structures of mammalian DNA methyltransferases (DNMTs). Functional domains in the N-terminal regions of DNMTs are shown and the conserved motifs in the C-terminal region are labelled. In the N-terminal region, the sub-domains include a proliferating cell nuclear antigen binding site (PBD), nuclear localisation signal region (NLS), plant homeo domain (PHD) like domain and PWWP domain (highly conserved proline-tryptophan-tryptophan-proline motif that is involved in protein-protein interactions) and bromo-adjacent homology domains (BAH). N- and C-terminal domains are linked by Gly-Lys dipeptides. Highly conserved C-terminal methyltransferase motifs are shown as thick black lines (indicated as I-X). (B) Domain structures of methyl-CpG binding proteins (MeCPs). Three families of characterised mammalian MeCPs include (1) the methyl-CpG binding domain proteins (MBDs) MBD1, MBD2, MBD3, MBD4 and MeCP2. (2) the structurally unrelated methyl-CpG binding zinc-finger proteins of the Kaiso family KAISO/ZBTB33, ZBTB4 and ZBTB38 and (3) the methyl-CpG binding SRA domain proteins of the UHRF family UHRF1 and its homologue UHRF2. Labelled sub-domains include MBD, methyl-CpG binding domain; TRD, trans-repressor domain; GR, E, P, amino acid repeats; BTB/POZ, broad complex, tramtrack, and bric à brac domains; ZF, zinc finger motifs; UBL, ubiquitin-like motif; PHD, Plant homeodomain and SRA, SET and Ring-associated domain. DNA binding regions are indicated. (C) Domain structures of ten-eleven translocation methylcytosine dioxygenases (TETs). Schematic representation of conserved domains of mouse Tet proteins is shown, including a double-stranded-helix (DSBH) fold (all Tets), cysteine-rich (Cys-rich) domain (all Tets) and CXXC zinc fingers (Tet1 and Tet3).
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Figure 2: Mediators of DNA methylation machinery. (A) Domain structures of mammalian DNA methyltransferases (DNMTs). Functional domains in the N-terminal regions of DNMTs are shown and the conserved motifs in the C-terminal region are labelled. In the N-terminal region, the sub-domains include a proliferating cell nuclear antigen binding site (PBD), nuclear localisation signal region (NLS), plant homeo domain (PHD) like domain and PWWP domain (highly conserved proline-tryptophan-tryptophan-proline motif that is involved in protein-protein interactions) and bromo-adjacent homology domains (BAH). N- and C-terminal domains are linked by Gly-Lys dipeptides. Highly conserved C-terminal methyltransferase motifs are shown as thick black lines (indicated as I-X). (B) Domain structures of methyl-CpG binding proteins (MeCPs). Three families of characterised mammalian MeCPs include (1) the methyl-CpG binding domain proteins (MBDs) MBD1, MBD2, MBD3, MBD4 and MeCP2. (2) the structurally unrelated methyl-CpG binding zinc-finger proteins of the Kaiso family KAISO/ZBTB33, ZBTB4 and ZBTB38 and (3) the methyl-CpG binding SRA domain proteins of the UHRF family UHRF1 and its homologue UHRF2. Labelled sub-domains include MBD, methyl-CpG binding domain; TRD, trans-repressor domain; GR, E, P, amino acid repeats; BTB/POZ, broad complex, tramtrack, and bric à brac domains; ZF, zinc finger motifs; UBL, ubiquitin-like motif; PHD, Plant homeodomain and SRA, SET and Ring-associated domain. DNA binding regions are indicated. (C) Domain structures of ten-eleven translocation methylcytosine dioxygenases (TETs). Schematic representation of conserved domains of mouse Tet proteins is shown, including a double-stranded-helix (DSBH) fold (all Tets), cysteine-rich (Cys-rich) domain (all Tets) and CXXC zinc fingers (Tet1 and Tet3).

Mentions: The methyltransferase enzymes DNMT1, DNMT3A and DNMT3B harmonise in the establishment and maintenance of DNA methylation patterns in mammals (Fig. 2A and Table 1). DNMT3A and DNMT3B are de novo methyltransferases that target cytosines of previously unmethylated CpG dinucleotides. These enzymes have an equal preference for hemimethylated and unmethylated DNA, which are essential for their roles in de novo methylation of the genome during development and for newly integrated retroviral sequences 48, 49. Following the first wave of genome-wide demethylation in the preimplantation embryo, Dnmt3a and Dnmt3b are highly expressed at implantation and re-establish a bimodal methylation pattern that effects more than 80% of the genome 48, whereas most CGIs are protected by unknown mechanisms and therefore remain unmodified 41. Genetic and functional analyses indicate that Dnmt3a and Dnmt3b have non-overlapping functions during development with different phenotypes and lethality stages 48, suggesting that each enzyme has regional specificity that reflects their respective N-terminal domains. Accordingly, Dnmt3a is necessary for maternal imprinting at differentially methylated regions, and Dnmt3b is required for methylation of pericentromeric repeats and CGIs on inactive X-chromosomes 50. Established DNA methylation patterns are stably preserved over cell divisions by DNA methyltransferase-1 (DNMT1), which is known as a maintenance enzyme that guards existing methylated sites through its preference for hemimethylated DNA 51. Dnmt1 is particularly present at high concentrations in dividing cells 51, localising perpetually to replication foci 52. Dnmt1 operates with its methylation co-factor UHRF1 (Np95) in protein complexes that constitute an enzymatic platform, providing a maintenance methyltransferase function for CpG methylation 53-55. In addition to its methyltransferase activity, DNMT1 has a proliferating cell nuclear antigen-interacting domain, replication-targeting region, cysteine-rich Zn2+-binding domain, nuclear localisation signal and polybromo-1 like protein domain 56, 57. It also contains an N-terminal region that is associated with various chromatin-associated proteins, including de novo methyltransferases, histone modifying enzymes and MeCPs. Among DNMTs, DNMT2 shows weak methyltransferase activity in vitro, and its depletion has little impact on global CpG methylation levels and no discernible effects on developmental phenotypes 51. Moreover, although DNMT3L (DNMT3-like) is catalytically inactive, it is highly expressed in germ and ES cells and acts as an obligatory cofactor for de novo methyltransferase in ES cells 58. Dnmt3L stimulates the methyltransferase activity of Dnmt3a or Dnmt3b through physical interaction 59-62. Crystallographic analyses of Dnmt3a and Dnmt3L indicate that these interactions may be mediated by a heterotetrameric complex formation 63, which may prevent Dnmt3a oligomerisation and heterochromatic localisation 64. A recent study showed that DNMT3L is a positive regulator of DNA methylation at gene bodies of housekeeping genes and a negative regulator of DNA methylation at promoters of bivalent genes in mouse ES cells, suggesting a dual role in ES cell differentiation 65.


DNA methylation, its mediators and genome integrity.

Meng H, Cao Y, Qin J, Song X, Zhang Q, Shi Y, Cao L - Int. J. Biol. Sci. (2015)

Mediators of DNA methylation machinery. (A) Domain structures of mammalian DNA methyltransferases (DNMTs). Functional domains in the N-terminal regions of DNMTs are shown and the conserved motifs in the C-terminal region are labelled. In the N-terminal region, the sub-domains include a proliferating cell nuclear antigen binding site (PBD), nuclear localisation signal region (NLS), plant homeo domain (PHD) like domain and PWWP domain (highly conserved proline-tryptophan-tryptophan-proline motif that is involved in protein-protein interactions) and bromo-adjacent homology domains (BAH). N- and C-terminal domains are linked by Gly-Lys dipeptides. Highly conserved C-terminal methyltransferase motifs are shown as thick black lines (indicated as I-X). (B) Domain structures of methyl-CpG binding proteins (MeCPs). Three families of characterised mammalian MeCPs include (1) the methyl-CpG binding domain proteins (MBDs) MBD1, MBD2, MBD3, MBD4 and MeCP2. (2) the structurally unrelated methyl-CpG binding zinc-finger proteins of the Kaiso family KAISO/ZBTB33, ZBTB4 and ZBTB38 and (3) the methyl-CpG binding SRA domain proteins of the UHRF family UHRF1 and its homologue UHRF2. Labelled sub-domains include MBD, methyl-CpG binding domain; TRD, trans-repressor domain; GR, E, P, amino acid repeats; BTB/POZ, broad complex, tramtrack, and bric à brac domains; ZF, zinc finger motifs; UBL, ubiquitin-like motif; PHD, Plant homeodomain and SRA, SET and Ring-associated domain. DNA binding regions are indicated. (C) Domain structures of ten-eleven translocation methylcytosine dioxygenases (TETs). Schematic representation of conserved domains of mouse Tet proteins is shown, including a double-stranded-helix (DSBH) fold (all Tets), cysteine-rich (Cys-rich) domain (all Tets) and CXXC zinc fingers (Tet1 and Tet3).
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Figure 2: Mediators of DNA methylation machinery. (A) Domain structures of mammalian DNA methyltransferases (DNMTs). Functional domains in the N-terminal regions of DNMTs are shown and the conserved motifs in the C-terminal region are labelled. In the N-terminal region, the sub-domains include a proliferating cell nuclear antigen binding site (PBD), nuclear localisation signal region (NLS), plant homeo domain (PHD) like domain and PWWP domain (highly conserved proline-tryptophan-tryptophan-proline motif that is involved in protein-protein interactions) and bromo-adjacent homology domains (BAH). N- and C-terminal domains are linked by Gly-Lys dipeptides. Highly conserved C-terminal methyltransferase motifs are shown as thick black lines (indicated as I-X). (B) Domain structures of methyl-CpG binding proteins (MeCPs). Three families of characterised mammalian MeCPs include (1) the methyl-CpG binding domain proteins (MBDs) MBD1, MBD2, MBD3, MBD4 and MeCP2. (2) the structurally unrelated methyl-CpG binding zinc-finger proteins of the Kaiso family KAISO/ZBTB33, ZBTB4 and ZBTB38 and (3) the methyl-CpG binding SRA domain proteins of the UHRF family UHRF1 and its homologue UHRF2. Labelled sub-domains include MBD, methyl-CpG binding domain; TRD, trans-repressor domain; GR, E, P, amino acid repeats; BTB/POZ, broad complex, tramtrack, and bric à brac domains; ZF, zinc finger motifs; UBL, ubiquitin-like motif; PHD, Plant homeodomain and SRA, SET and Ring-associated domain. DNA binding regions are indicated. (C) Domain structures of ten-eleven translocation methylcytosine dioxygenases (TETs). Schematic representation of conserved domains of mouse Tet proteins is shown, including a double-stranded-helix (DSBH) fold (all Tets), cysteine-rich (Cys-rich) domain (all Tets) and CXXC zinc fingers (Tet1 and Tet3).
Mentions: The methyltransferase enzymes DNMT1, DNMT3A and DNMT3B harmonise in the establishment and maintenance of DNA methylation patterns in mammals (Fig. 2A and Table 1). DNMT3A and DNMT3B are de novo methyltransferases that target cytosines of previously unmethylated CpG dinucleotides. These enzymes have an equal preference for hemimethylated and unmethylated DNA, which are essential for their roles in de novo methylation of the genome during development and for newly integrated retroviral sequences 48, 49. Following the first wave of genome-wide demethylation in the preimplantation embryo, Dnmt3a and Dnmt3b are highly expressed at implantation and re-establish a bimodal methylation pattern that effects more than 80% of the genome 48, whereas most CGIs are protected by unknown mechanisms and therefore remain unmodified 41. Genetic and functional analyses indicate that Dnmt3a and Dnmt3b have non-overlapping functions during development with different phenotypes and lethality stages 48, suggesting that each enzyme has regional specificity that reflects their respective N-terminal domains. Accordingly, Dnmt3a is necessary for maternal imprinting at differentially methylated regions, and Dnmt3b is required for methylation of pericentromeric repeats and CGIs on inactive X-chromosomes 50. Established DNA methylation patterns are stably preserved over cell divisions by DNA methyltransferase-1 (DNMT1), which is known as a maintenance enzyme that guards existing methylated sites through its preference for hemimethylated DNA 51. Dnmt1 is particularly present at high concentrations in dividing cells 51, localising perpetually to replication foci 52. Dnmt1 operates with its methylation co-factor UHRF1 (Np95) in protein complexes that constitute an enzymatic platform, providing a maintenance methyltransferase function for CpG methylation 53-55. In addition to its methyltransferase activity, DNMT1 has a proliferating cell nuclear antigen-interacting domain, replication-targeting region, cysteine-rich Zn2+-binding domain, nuclear localisation signal and polybromo-1 like protein domain 56, 57. It also contains an N-terminal region that is associated with various chromatin-associated proteins, including de novo methyltransferases, histone modifying enzymes and MeCPs. Among DNMTs, DNMT2 shows weak methyltransferase activity in vitro, and its depletion has little impact on global CpG methylation levels and no discernible effects on developmental phenotypes 51. Moreover, although DNMT3L (DNMT3-like) is catalytically inactive, it is highly expressed in germ and ES cells and acts as an obligatory cofactor for de novo methyltransferase in ES cells 58. Dnmt3L stimulates the methyltransferase activity of Dnmt3a or Dnmt3b through physical interaction 59-62. Crystallographic analyses of Dnmt3a and Dnmt3L indicate that these interactions may be mediated by a heterotetrameric complex formation 63, which may prevent Dnmt3a oligomerisation and heterochromatic localisation 64. A recent study showed that DNMT3L is a positive regulator of DNA methylation at gene bodies of housekeeping genes and a negative regulator of DNA methylation at promoters of bivalent genes in mouse ES cells, suggesting a dual role in ES cell differentiation 65.

Bottom Line: DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability.DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins.Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: 1. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China; ; 2. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China.

ABSTRACT
DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability. DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins. Multiple forms of DNA methylation are recognised by methyl-CpG binding proteins (MeCPs), which play vital roles in chromatin-based transcriptional regulation, DNA repair and replication. Accordingly, defects in DNA methylation and its mediators may cause silencing of tumour suppressor genes and misregulation of multiple cell cycles, DNA repair and chromosome stability genes, and hence contribute to genome instability in various human diseases, including cancer. Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.

Show MeSH
Related in: MedlinePlus