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BioAssay: AID 686973

Summary of a probe development effort to identify inhibitors of 5-meCpG-binding domain protein 2 (MBD2)-DBD binding to methylated oligonucleotide

Name: Summary of a probe development effort to identify inhibitors of 5-meCpG-binding domain protein 2 (MBD2)-DBD binding to methylated oligonucleotide. ..more
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AID: 686973
Data Source: The Scripps Research Institute Molecular Screening Center (MBD2-CPGDNA_INH_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2013-05-09
Target
Depositor Specified Assays
AIDNameTypeComment
686964TRFRET-based biochemical primary high throughput screening assay to identify inhibitors of 5-meCpG-binding domain protein 2 (MBD2)-DBD binding to methylated oligonucleotidescreeningPrimary screen(MBD2-CPGDNA INH in singlecate)
687016Counterscreen for inhibitors of 5-meCpG-binding domain protein 2 (MBD2): TRFRET-based biochemical primary high throughput screening assay to identify inhibitors of binding of ubiquitin-like with PHD and ring finger domains 1 (UHRF1) to methylated oligonucleotidescreening
720530Counterscreen for inhibitors of 5-meCpG-binding domain protein 2 (MBD2): TRFRET-based biochemical high throughput screening assay to identify inhibitors of binding of ubiquitin-like with PHD and ring finger domains 1 (UHRF1) to methylated oligonucleotidescreening
720531TRFRET-based biochemical high throughput confirmation assay to identify inhibitors of 5-meCpG-binding domain protein 2 (MBD2)-DBD binding to methylated oligonucleotidescreening
720644Counterscreen for inhibitors of 5-meCpG-binding domain protein 2 (MBD2): TRFRET-based biochemical high throughput dose response assay to identify inhibitors of binding of ubiquitin-like with PHD and ring finger domains 1 (UHRF1) to methylated oligonucleotideconfirmatory
720645TRFRET-based biochemical high throughput dose response assay to identify inhibitors of 5-meCpG-binding domain protein 2 (MBD2)-DBD binding to methylated oligonucleotideconfirmatory
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Bill Nelson
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R03 MH098712-01
Grant Proposal PI: Bill Nelson
External Assay ID: MBD2-CPGDNA_INH_SUMMARY

Name: Summary of a probe development effort to identify inhibitors of 5-meCpG-binding domain protein 2 (MBD2)-DBD binding to methylated oligonucleotide.

Description:

Of all the somatic genome changes that accumulate during the pathogenesis of human cancers, only changes in DNA methylation appear to occur consistently (virtually all cases), to arise early (first appearing in preneoplastic lesions), and to be potentially reversible (the DNA sequence remains intact) (1-4). One such change in DNA methylation, increased CpG dinucleotide methylation at CpG islands encompassing the transcriptional regulatory regions of many genes, leads to the transcriptional "silencing" of critical cancer genes (2, 5-6). CpG island hypermethylation has been reported to inhibit gene transcription by interfering with the binding and/or function of transcriptional trans-activators, or by recruiting 5-meCpG-binding domain (MBD) family proteins capable of mediating transcriptional repression (7). As many as 500 or more genes are epigenetically "silenced" in most human cancers. Two MBD family proteins have been implicated in the silencing of genes carrying abnormally hypermethylated CpG island sequences, MECP2 and MBD2. MBD2 binds 5-meCpG-DNA and is a component of a 1 MD transcription repression complex that also contains a chromatin remodeling complex subunits, histone-binding proteins, and a helicase/ATPase domain (8). Evidence suggests that MBD2-containing complexes are responsible for transcriptional repression accompanying somatic hypermethylation at ?-class glutathione S-transferase 1 (GSTP1), the most common genome change yet reported for prostate cancer, and a common alteration in breast and liver cancers (9-11). The goal of this project is the discovery and characterization of small molecule inhibitors of epigenetic gene silencing mediated by MBD2 and thus to identify compounds that will be able to reactivate the silenced genes in cancer cells, restoring gene function.

References:

1. Brooks, J. D., Weinstein, M., Lin, X., Sun, Y., Pin, S. S., Bova, G. S., Epstein, J. I., Isaacs, W. B., and Nelson, W. G. (1998) CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia, Cancer Epidemiol Biomarkers Prev 7, 531-536.
2. Herman, J. G., and Baylin, S. B. (2003) Gene silencing in cancer in association with promoter hypermethylation, N Engl J Med 349, 2042-2054.
3. Lin, X., Tascilar, M., Lee, W. H., Vles, W. J., Lee, B. H., Veeraswamy, R., Asgari, K., Freije, D., van Rees, B., Gage, W. R., Bova, G. S., Isaacs, W. B., Brooks, J. D., DeWeese, T. L., De Marzo, A. M., and Nelson, W. G. (2001) GSTP1 CpG island hypermethylation is responsible for the absence of GSTP1 expression in human prostate cancer cells, Am J Pathol 159, 1815-1826.
4. Nakayama, M., Bennett, C. J., Hicks, J. L., Epstein, J. I., Platz, E. A., Nelson, W. G., and De Marzo, A. M. (2003) Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection, Am J Pathol 163, 923-933.
5. Antequera, F., and Bird, A. (1993) Number of CpG islands and genes in human and mouse, Proc Natl Acad Sci U S A 90, 11995-11999.
6. Bird, A. P. (1986) CpG-rich islands and the function of DNA methylation, Nature 321, 209-213.
7. Bird, A. P., and Wolffe, A. P. (1999) Methylation-induced repression--belts, braces, and chromatin, Cell 99, 451-454.
8. Feng, Q., and Zhang, Y. (2001) The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes, Genes Dev 15, 827-832.
9. Bakker, J., Lin, X., and Nelson, W. G. (2002) Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells, J Biol Chem 277, 22573-22580.
10. Lin, X., and Nelson, W. G. (2003) Methyl-CpG-binding domain protein-2 mediates transcriptional repression associated with hypermethylated GSTP1 CpG islands in MCF-7 breast cancer cells, Cancer Res 63, 498-504.
11. Singal, R., van Wert, J., and Bashambu, M. (2001) Cytosine methylation represses glutathione S-transferase P1 (GSTP1) gene expression in human prostate cancer cells, Cancer Res 61, 4820-4826.

Keywords:

Summary, Summary AID, Methyl-CpG binding domain, MBD2, DNA binding domain, MBD2-CpGDNA, MBD2-CPGDNA, MBD2-DBD, MBD2-MBD, FAM CpG DNA, Lanthascreen Tb Anti-HIS antibody, gene silencing, epigenetic gene silencing, cancer, GSTP1, glutathione S-transferase 1, pi class glutathione S-transferase 1, FAM, carboxyfluorescene, primary, singlicate, confirmation, triplicate, dose response, biochemical, antagonist, inhibit, inhibitor, inhibition, inh, FRET, fluorescence, HTS, high throughput screen, 1536, Scripps, Scripps Florida, MLSMR, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Additional Information
Grant Number: 1 R03 MH098712-01

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