Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells

Bestor, Timothy H.; Laudano, Andrew P.; Mattaliano, Robert J.; Ingram, Vernon M.

doi:10.1016/0022-2836(88)90122-2

Cited by 801 publications

(293 citation statements)

References 52 publications

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“…The target cytosine is extruded from the double helix into the active site cleft of the enzyme where it can be reacted upon by a conserved active site cysteine . DNMT1 was the ®rst methyltransferase to be discovered (Bestor et al, 1988) while the DNMT3 family was only recently discovered and characterized.…”

Section: The Dna Methylation Machinerymentioning

confidence: 99%

DNA methylation, methyltransferases, and cancer

2001

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The ®eld of epigenetics has recently moved to the forefront of studies relating to diverse processes such as transcriptional regulation, chromatin structure, genome integrity, and tumorigenesis. Recent work has revealed how DNA methylation and chromatin structure are linked at the molecular level and how methylation anomalies play a direct causal role in tumorigenesis and genetic disease. Much new information has also come to light regarding the cellular methylation machinery, known as the DNA methyltransferases, in terms of their roles in mammalian development and the types of proteins they are known to interact with. This information has forced a new view for the role of DNA methyltransferases. Rather than enzymes that act in isolation to copy methylation patterns after replication, the types of interactions discovered thus far indicate that DNA methyltransferases may be components of larger complexes actively involved in transcriptional control and chromatin structure modulation. These new ®ndings will likely enhance our understanding of the myriad roles of DNA methylation in disease as well as point the way to novel therapies to prevent or repair these defects. Oncogene (2001) 20, 3139 ± 3155.

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Section: The Dna Methylation Machinerymentioning

confidence: 99%

DNA methylation, methyltransferases, and cancer

2001

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“…DNA methylation is catalysed by the activation of several DNA methyltransferases (Dnmts) during cell replication. There are at least three different major catalytically active Dnmts, Dnmt1 (Bestor et al, 1988), Dnmt3a and Dnmt3b (Okano et al, 1998), which are involved in cellular DNA methylation. In somatic cells, Dnmt1 has the maintenance methyltransferase activity as a consequence of its affinity for hemimethylated DNA.…”

Section: Introductionmentioning

confidence: 99%

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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The Ets transcription factor PU.1 is a hematopoietic master regulator essential for the development of myeloid and B-cell lineages. As we previously reported, PU.1 sometimes represses transcription on forming a complex with mSin3A-histone deacetyl transferase-MeCP2. Here, we show an interaction between PU.1 and DNA methyltransferases, DNA methyltransferase (Dnmt)3a and Dnmt3b (Dnmt3s). Glutathione-S-transferase pulldown assay revealed that PU.1 directly interacted with the ATRX domain of Dnmt3s through the ETS domain. Dnmt3s repressed the transcriptional activity of PU.1 on a reporter construct with trimerized PU.1-binding sites. The repression was recovered by addition of 5-aza-deoxycitidine, a DNA methyltransferase inhibitor, but not trichostatin A, a histone deacetylase inhibitor. Bisulfite sequence analysis revealed that several CpG sites in the promoter region neighboring the PU.1-binding sites were methylated when Dnmt3s were coexpressed with PU.1. We also showed that the CpG sites in the p16 INK4A promoter were methylated by overexpression of PU.1 in NIH3T3 cells, accompanied by a downregulation of p16 INK4A gene expression. These results suggest that PU.1 may downregulate its target genes through an epigenetic modification such as DNA methylation.

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“…Most have a C-terminal catalytic domain containing the 10 DNA methyltransferase signature sequence motifs found in procaryotes (Lauster et al, 1989;Posfai et al, 1989), and an N-terminal domain involved in proteinprotein interactions. DNMT1 has a preference for hemimethylated DNA and is required for maintenance of methylation patterns in embryos and adult tissues (Bestor et al, 1988;Li et al, 1992). DNMT2 has only the C-terminal domain and, despite the presence of all of the enzymatic signature motifs, it has no detectable methyltransferase activity (Okano et al, 1998b).…”

Section: Introductionmentioning

confidence: 99%

DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras

2003

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Transcriptional silencing of tumor suppressor genes in association with DNA methylation contributes to malignant transformation. However, the specific DNA methyltransferases that initiate this process are unknown. Here we show that a de novo DNA methyltransferase, DNMT3b, substantially contributes to the oncogenic phenotype in a lung cancer model. Normal human bronchial epithelial (NHBE) cells expressing telomerase, SV40 large T antigen, and activated Ras were immortal, formed colonies in soft agar, and expressed DNMT3b. Antisense suppression of DNMT3b prevented soft agar growth. Furthermore, mouse embryo fibroblasts expressing T antigen and Ras formed soft agar colonies and large tumors, but fibroblasts from Dnmt3b À/À mice did not grow in soft agar and were much less tumorigenic in vivo. The tumor suppressor genes, FHIT, TSLC1, and RASSF1A were downregulated in transformed NHBE cells, and antisense DNMT3b treatment resulted in reexpression of FHIT and TSLC1. While expression of TSCL1 correlated with methylation of CpG dinucleotides in its promoter region, the expression of FHIT did not, suggesting that DNMT3b may silence genes by several mechanisms including direct DNA methylation or recruitment of proteins that modify chromatin. Regardless of mechanism, our data indicate that DNMT3b plays an important role in transformation.

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Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells

Cited by 801 publications

References 52 publications

DNA methylation, methyltransferases, and cancer

DNA methylation, methyltransferases, and cancer

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras

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