6 results on '"Sagum, Cari"'
Search Results
2. discovery and characterization of a cellular potent positive allosteric modulator of the polycomb repressive complex 1 chromodomain cbx7
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Lamb, Kelsey N., Wang, Jingkui, Sagum, Cari, Stanton, Benjamin Z., Bedford, Mark T., Pearce, Kenneth H., Kenakin, Terry P., Kireev, Dmitri B., Wang, Gang Greg, James, Lindsey I., Bell, Oliver, Bsteh, Daniel, Frye, Stephen V., Dishman, Sarah N., Moussa, Hagar F., Fan, Huitao, Stuckey, Jacob I., Norris, Jacqueline L., Cholensky, Stephanie H., and Li, Dongxu
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Pharmacology ,Peptidomimetic ,Allosteric modulator ,Clinical Biochemistry ,macromolecular substances ,Biochemistry ,PRC1 ,Chromatin ,Chromodomain ,Drug Discovery ,Psychological repression ,Molecular Medicine ,RNA ,Gene expression ,Molecular Biology ,Biology - Abstract
Summary Polycomb-directed repression of gene expression is frequently misregulated in human diseases. A quantitative and target-specific cellular assay was utilized to discover the first potent positive allosteric modulator (PAM) peptidomimetic, UNC4976, of nucleic acid binding by CBX7, a chromodomain methyl-lysine reader of Polycomb repressive complex 1. The PAM activity of UNC4976 resulted in enhanced efficacy across three orthogonal cellular assays by simultaneously antagonizing H3K27me3-specific recruitment of CBX7 to target genes while increasing non-specific binding to DNA and RNA. PAM activity thereby reequilibrates PRC1 away from H3K27me3 target regions. Together, our discovery and characterization of UNC4976 not only revealed the most cellularly potent PRC1-specific chemical probe to date, but also uncovers a potential mechanism of Polycomb regulation with implications for non-histone lysine methylated interaction partners.
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- 2019
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3. Histone peptide microarray screen of chromo and Tudor domains defines new histone lysine methylation interactions.
- Author
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Shanle, Erin K., Shinsky, Stephen A., Bridgers, Joseph B., Bae, Narkhyun, Sagum, Cari, Krajewski, Krzysztof, Rothbart, Scott B., Bedford, Mark T., and Strahl, Brian D.
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HISTONE methylation ,POST-translational modification ,CHROMATIN ,PROTEIN microarrays ,PROTEIN structure - Abstract
Background: Histone posttranslational modifications (PTMs) function to regulate chromatin structure and function in part through the recruitment of effector proteins that harbor specialized "reader" domains. Despite efforts to elucidate reader domain--PTM interactions, the influence of neighboring PTMs and the target specificity of many reader domains is still unclear. The aim of this study was to use a high-throughput histone peptide microarray platform to interrogate 83 known and putative histone reader domains from the chromo and Tudor domain families to identify their interactions and characterize the influence of neighboring PTMs on these interactions. Results: Nearly a quarter of the chromo and Tudor domains screened showed interactions with histone PTMs by peptide microarray, revealing known and several novel methyllysine interactions. Specifically, we found that the CBX/ HP1 chromodomains that recognize H3K9me also recognize H3K23me2/3--a poorly understood histone PTM. We also observed that, in addition to their interaction with H3K4me3, Tudor domains of the Spindlin family also recognized H4K20me3--a previously uncharacterized interaction. Several Tudor domains also showed novel interactions with H3K4me as well. Conclusions: These results provide an important resource for the epigenetics and chromatin community on the interactions of many human chromo and Tudor domains. They also provide the basis for additional studies into the functional significance of the novel interactions that were discovered. [ABSTRACT FROM AUTHOR]
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- 2017
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4. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain.
- Author
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James, Lindsey I, Barsyte-Lovejoy, Dalia, Zhong, Nan, Krichevsky, Liubov, Korboukh, Victoria K, Herold, J Martin, MacNevin, Christopher J, Norris, Jacqueline L, Sagum, Cari A, Tempel, Wolfram, Marcon, Edyta, Guo, Hongbo, Gao, Cen, Huang, Xi-Ping, Duan, Shili, Emili, Andrew, Greenblatt, Jack F, Kireev, Dmitri B, Jin, Jian, and Janzen, William P
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DROSOPHILA ,GENE regulatory networks ,CHROMATIN ,DNA damage ,DNA repair ,APOPTOSIS ,BRAIN tumors ,X-ray crystallography - Abstract
We describe the discovery of UNC1215, a potent and selective chemical probe for the methyllysine (Kme) reading function of L3MBTL3, a member of the malignant brain tumor (MBT) family of chromatin-interacting transcriptional repressors. UNC1215 binds L3MBTL3 with a K
d of 120 nM, competitively displacing mono- or dimethyllysine-containing peptides, and is greater than 50-fold more potent toward L3MBTL3 than other members of the MBT family while also demonstrating selectivity against more than 200 other reader domains examined. X-ray crystallography identified a unique 2:2 polyvalent mode of interaction between UNC1215 and L3MBTL3. In cells, UNC1215 is nontoxic and directly binds L3MBTL3 via the Kme-binding pocket of the MBT domains. UNC1215 increases the cellular mobility of GFP-L3MBTL3 fusion proteins, and point mutants that disrupt the Kme-binding function of GFP-L3MBTL3 phenocopy the effects of UNC1215 on localization. Finally, UNC1215 was used to reveal a new Kme-dependent interaction of L3MBTL3 with BCLAF1, a protein implicated in DNA damage repair and apoptosis. [ABSTRACT FROM AUTHOR]- Published
- 2013
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5. Acetylation on histone H3 lysine 9 mediates a switch from transcription initiation to elongation.
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Gates, Leah A., Jiejun Shi, Rohira, Aarti D., Qin Feng, Bokai Zhu, Bedford, Mark T., Sagum, Cari A., Sung Yun Jung, Jun Qin, Ming-Jer Tsai, Tsai, Sophia Y., Wei Li, Foulds, Charles E., and O'Malley, Bert W.
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ACETYLATION , *HISTONES , *ELONGATION factors (Biochemistry) , *GENETIC transcription , *CHROMATIN - Abstract
The transition from transcription initiation to elongation is a key regulatory step in gene expression, which requires RNA polymerase II (pol II) to escape promoter proximal pausing on chromatin. Although elongation factors promote pause release leading to transcription elongation, the role of epigenetic modifications during this critical transition step is poorly understood. Two histone marks on histone H3, lysine 4 trimethylation (H3K4me3) and lysine 9 acetylation (H3K9ac), co-localize on active gene promoters and are associated with active transcription. H3K4me3 can promote transcription initiation, yet the functional role of H3K9ac is much less understood. We hypothesized that H3K9ac may function downstream of transcription initiation by recruiting proteins important for the next step of transcription. Here, we describe a functional role for H3K9ac in promoting pol II pause release by directly recruiting the super elongation complex (SEC) to chromatin. H3K9ac serves as a substrate for direct binding of the SEC, as does acetylation of histone H4 lysine 5 to a lesser extent. Furthermore, lysine 9 on histone H3 is necessary for maximal pol II pause release through SEC action, and loss of H3K9ac increases the pol II pausing index on a subset of genes in HeLa cells. At select gene promoters, H3K9ac loss or SEC depletion reduces gene expression and increases paused pol II occupancy.Wetherefore propose that an ordered histone code can promote progression through the transcription cycle, providing new mechanistic insight indicating that SEC recruitment to certain acetylated histones on a subset of genes stimulates the subsequent release of paused pol II needed for transcription elongation. [ABSTRACT FROM AUTHOR]
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- 2017
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6. Reprogramming CBX8-PRC1 function with a positive allosteric modulator.
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Suh, Junghyun L., Bsteh, Daniel, Hart, Bryce, Si, Yibo, Weaver, Tyler M., Pribitzer, Carina, Lau, Roy, Soni, Shivani, Ogana, Heather, Rectenwald, Justin M., Norris, Jacqueline L., Cholensky, Stephanie H., Sagum, Cari, Umana, Jessica D., Li, Dongxu, Hardy, Brian, Bedford, Mark T., Mumenthaler, Shannon M., Lenz, Heinz-Josef, and Kim, Yong-Mi
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CELL differentiation , *NUCLEIC acids , *CELL lines , *WNT signal transduction , *CHROMATIN , *DIFFUSE large B-cell lymphomas , *CANCER cells - Abstract
Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small-molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity. • Structure-based design of selective, high-affinity chemical probe against CBX8 • Cellular reporter identifies UNC7040, a PAM of CBX8 • PAM activity blocks H3K27me3 binding and enhances CBX8 affinity for nucleic acids • UNC7040 evicts PRC1 from H3K27me3 targets triggering DLBCL cell differentiation Suh et al. describe the discovery of UNC7040, a potent, cellularly active positive allosteric modulator of CBX8. In addition to blocking H3K27me3 binding, UNC7040 enhances CBX8 interaction with nucleic acids leading to efficient canonical PRC1 eviction and activation of Polycomb target genes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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