Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair

Ya-Qiang Li, Ping-Zhu Zhou, Xiu-Dan Zheng, Colum Walsh, Guo-Liang Xu

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

While methylcytosines serve as the fifth base encoding epigenetic information, they are also a dangerous endogenous mutagen due to their intrinsic instability. Methylcytosine undergoes spontaneous deamination, at a rate much higher than cytosine, to generate thymine. In mammals, two repair enzymes, thymine DNA glycosylase (TDG) and methyl-CpG binding domain 4 (MBD4), have evolved to counteract the mutagenic effect of methylcytosines. Both recognize G/T mismatches arising from methylcytosine deamination and initiate base-excision repair that corrects them to G/C pairs. However, the mechanism by which the methylation status of the repaired cytosines is restored has remained unknown. We show here that the DNA methyltransferase Dnmt3a interacts with TDG. Both the PWWP domain and the catalytic domain of Dnmt3a are able to mediate the interaction with TDG at its N-terminus. The interaction affects the enzymatic activity of both proteins: Dnmt3a positively regulates the glycosylase activity of TDG, while TDG inhibits the methylation activity of Dnmt3a in vitro. These data suggest a mechanistic link between DNA repair and remethylation at sites affected by methylcytosine deamination.
LanguageEnglish
Pages390-400
JournalNucleic Acids Research
Volume35
Issue number2
DOIs
Publication statusPublished - Jan 2007

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Thymine DNA Glycosylase
DNA Methylation
DNA Repair
Deamination
Cytosine
Methylation
Thymine
Mutagens
Methyltransferases
Epigenomics
Mammals
Catalytic Domain
DNA
Enzymes

Cite this

Li, Ya-Qiang ; Zhou, Ping-Zhu ; Zheng, Xiu-Dan ; Walsh, Colum ; Xu, Guo-Liang. / Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair. In: Nucleic Acids Research. 2007 ; Vol. 35, No. 2. pp. 390-400.
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abstract = "While methylcytosines serve as the fifth base encoding epigenetic information, they are also a dangerous endogenous mutagen due to their intrinsic instability. Methylcytosine undergoes spontaneous deamination, at a rate much higher than cytosine, to generate thymine. In mammals, two repair enzymes, thymine DNA glycosylase (TDG) and methyl-CpG binding domain 4 (MBD4), have evolved to counteract the mutagenic effect of methylcytosines. Both recognize G/T mismatches arising from methylcytosine deamination and initiate base-excision repair that corrects them to G/C pairs. However, the mechanism by which the methylation status of the repaired cytosines is restored has remained unknown. We show here that the DNA methyltransferase Dnmt3a interacts with TDG. Both the PWWP domain and the catalytic domain of Dnmt3a are able to mediate the interaction with TDG at its N-terminus. The interaction affects the enzymatic activity of both proteins: Dnmt3a positively regulates the glycosylase activity of TDG, while TDG inhibits the methylation activity of Dnmt3a in vitro. These data suggest a mechanistic link between DNA repair and remethylation at sites affected by methylcytosine deamination.",
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Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair. / Li, Ya-Qiang; Zhou, Ping-Zhu; Zheng, Xiu-Dan; Walsh, Colum; Xu, Guo-Liang.

In: Nucleic Acids Research, Vol. 35, No. 2, 01.2007, p. 390-400.

Research output: Contribution to journalArticle

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AB - While methylcytosines serve as the fifth base encoding epigenetic information, they are also a dangerous endogenous mutagen due to their intrinsic instability. Methylcytosine undergoes spontaneous deamination, at a rate much higher than cytosine, to generate thymine. In mammals, two repair enzymes, thymine DNA glycosylase (TDG) and methyl-CpG binding domain 4 (MBD4), have evolved to counteract the mutagenic effect of methylcytosines. Both recognize G/T mismatches arising from methylcytosine deamination and initiate base-excision repair that corrects them to G/C pairs. However, the mechanism by which the methylation status of the repaired cytosines is restored has remained unknown. We show here that the DNA methyltransferase Dnmt3a interacts with TDG. Both the PWWP domain and the catalytic domain of Dnmt3a are able to mediate the interaction with TDG at its N-terminus. The interaction affects the enzymatic activity of both proteins: Dnmt3a positively regulates the glycosylase activity of TDG, while TDG inhibits the methylation activity of Dnmt3a in vitro. These data suggest a mechanistic link between DNA repair and remethylation at sites affected by methylcytosine deamination.

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