Association of Dnmt3a and Thymine DNA Glycosylase Links DNA Methylation with Base-excision Repair

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2006 Dec 19

PMID 17175537

Citations 58

Authors

Ya-Qiang Li

Ping-Zhu Zhou

Xiu-Dan Zheng

Colum P Walsh

Guo-Liang Xu

Affiliations

Soon will be listed here.

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.

Citing Articles

scRNA-seq revealed transcriptional signatures of human umbilical cord primitive stem cells and their germ lineage origin regulated by imprinted genes.

Jarczak J, Bujko K, Ratajczak M, Kucia M Sci Rep. 2024; 14(1):29264.

PMID: 39587190 PMC: 11589151. DOI: 10.1038/s41598-024-79810-4.

The Role of DNMT Methyltransferases and TET Dioxygenases in the Maintenance of the DNA Methylation Level.

Davletgildeeva A, Kuznetsov N Biomolecules. 2024; 14(9).

PMID: 39334883 PMC: 11430729. DOI: 10.3390/biom14091117.

Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.

Rautajoki K, Jaatinen S, Hartewig A, Tiihonen A, Annala M, Salonen I Acta Neuropathol Commun. 2023; 11(1):176.

PMID: 37932833 PMC: 10629206. DOI: 10.1186/s40478-023-01669-9.

Unlocking the secrets: the power of methylation-based cfDNA detection of tissue damage in organ systems.

Zhang L, Li J Clin Epigenetics. 2023; 15(1):168.

PMID: 37858233 PMC: 10588141. DOI: 10.1186/s13148-023-01585-8.

Domain Structure of the Dnmt1, Dnmt3a, and Dnmt3b DNA Methyltransferases.

Tajima S, Suetake I, Takeshita K, Nakagawa A, Kimura H, Song J Adv Exp Med Biol. 2022; 1389:45-68.

PMID: 36350506 PMC: 11025882. DOI: 10.1007/978-3-031-11454-0_3.

References

Nguyen T, Goodrich J . Protein-protein interaction assays: eliminating false positive interactions. Nat Methods. 2006; 3(2):135-9. PMC: 2730730. DOI: 10.1038/nmeth0206-135. View

Cooper D, Youssoufian H . The CpG dinucleotide and human genetic disease. Hum Genet. 1988; 78(2):151-5. DOI: 10.1007/BF00278187. View

Xie Z, Huang Y, Chen Z, Riggs A, Ding J, Gowher H . Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L. Hum Mol Genet. 2006; 15(9):1375-85. DOI: 10.1093/hmg/ddl059. View

Reik W, Kelsey G, Walter J . Dissecting de novo methylation. Nat Genet. 1999; 23(4):380-2. DOI: 10.1038/70476. View

Lindahl T, Wood R . Quality control by DNA repair. Science. 1999; 286(5446):1897-905. DOI: 10.1126/science.286.5446.1897. View

Waters T, Swann P . Thymine-DNA glycosylase and G to A transition mutations at CpG sites. Mutat Res. 2000; 462(2-3):137-47. DOI: 10.1016/s1383-5742(00)00031-4. View

Roth M, Jeltsch A . Biotin-avidin microplate assay for the quantitative analysis of enzymatic methylation of DNA by DNA methyltransferases. Biol Chem. 2000; 381(3):269-72. DOI: 10.1515/BC.2000.035. View

Bestor T . The DNA methyltransferases of mammals. Hum Mol Genet. 2000; 9(16):2395-402. DOI: 10.1093/hmg/9.16.2395. View

Wood R, Mitchell M, Sgouros J, Lindahl T . Human DNA repair genes. Science. 2001; 291(5507):1284-9. DOI: 10.1126/science.1056154. View

10.

Scharer O, Jiricny J . Recent progress in the biology, chemistry and structural biology of DNA glycosylases. Bioessays. 2001; 23(3):270-81. DOI: 10.1002/1521-1878(200103)23:3<270::AID-BIES1037>3.0.CO;2-J. View

11.

Nakamura N, Hart D, Frank C, Marchuk L, Shrive N, Ota N . Efficient transfer of intact oligonucleotides into the nucleus of ligament scar fibroblasts by HVJ-cationic liposomes is correlated with effective antisense gene inhibition. J Biochem. 2001; 129(5):755-9. DOI: 10.1093/oxfordjournals.jbchem.a002916. View

12.

Fuks F, Burgers W, Godin N, Kasai M, Kouzarides T . Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J. 2001; 20(10):2536-44. PMC: 125250. DOI: 10.1093/emboj/20.10.2536. View

13.

Gowher H, Jeltsch A . Enzymatic properties of recombinant Dnmt3a DNA methyltransferase from mouse: the enzyme modifies DNA in a non-processive manner and also methylates non-CpG [correction of non-CpA] sites. J Mol Biol. 2001; 309(5):1201-8. DOI: 10.1006/jmbi.2001.4710. View

14.

Nilsen H, Krokan H . Base excision repair in a network of defence and tolerance. Carcinogenesis. 2001; 22(7):987-98. DOI: 10.1093/carcin/22.7.987. View

15.

Hardeland U, Bentele M, Lettieri T, Steinacher R, Jiricny J, Schar P . Thymine DNA glycosylase. Prog Nucleic Acid Res Mol Biol. 2001; 68:235-53. DOI: 10.1016/s0079-6603(01)68103-0. View

16.

Bourchis D, Xu G, Lin C, Bollman B, Bestor T . Dnmt3L and the establishment of maternal genomic imprints. Science. 2001; 294(5551):2536-9. DOI: 10.1126/science.1065848. View

17.

Sved J, Bird A . The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model. Proc Natl Acad Sci U S A. 1990; 87(12):4692-6. PMC: 54183. DOI: 10.1073/pnas.87.12.4692. View

18.

Jones P, Rideout 3rd W, Shen J, Spruck C, Tsai Y . Methylation, mutation and cancer. Bioessays. 1992; 14(1):33-6. DOI: 10.1002/bies.950140107. View

19.

Neddermann P, Jiricny J . The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells. J Biol Chem. 1993; 268(28):21218-24. View

20.

Neddermann P, Gallinari P, Lettieri T, Schmid D, Truong O, Hsuan J . Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase. J Biol Chem. 1996; 271(22):12767-74. DOI: 10.1074/jbc.271.22.12767. View