| Structural highlights
Function
CBX4_HUMAN E3 SUMO-protein ligase which facilitates SUMO1 conjugation by UBE2I. Involved in the sumoylation of HNRNPK, a p53/TP53 transcriptional coactivator, hence indirectly regulates p53/TP53 transcriptional activation resulting in p21/CDKN1A expression.[1] [2] [3] [4] [5] Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility.[6] [7] [8] [9] [10]
Publication Abstract from PubMed
We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a Kd of approximately 100 nM for each, and is 6- to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects.
A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1.,Stuckey JI, Dickson BM, Cheng N, Liu Y, Norris JL, Cholensky SH, Tempel W, Qin S, Huber KG, Sagum C, Black K, Li F, Huang XP, Roth BL, Baughman BM, Senisterra G, Pattenden SG, Vedadi M, Brown PJ, Bedford MT, Min J, Arrowsmith CH, James LI, Frye SV Nat Chem Biol. 2016 Mar;12(3):180-7. doi: 10.1038/nchembio.2007. Epub 2016 Jan, 25. PMID:26807715[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kagey MH, Melhuish TA, Wotton D. The polycomb protein Pc2 is a SUMO E3. Cell. 2003 Apr 4;113(1):127-37. PMID:12679040
- ↑ Long J, Zuo D, Park M. Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin. J Biol Chem. 2005 Oct 21;280(42):35477-89. Epub 2005 Aug 1. PMID:16061479 doi:http://dx.doi.org/M504477200
- ↑ Roscic A, Moller A, Calzado MA, Renner F, Wimmer VC, Gresko E, Ludi KS, Schmitz ML. Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2. Mol Cell. 2006 Oct 6;24(1):77-89. PMID:17018294 doi:http://dx.doi.org/S1097-2765(06)00563-6
- ↑ Vandamme J, Volkel P, Rosnoblet C, Le Faou P, Angrand PO. Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells. Mol Cell Proteomics. 2011 Apr;10(4):M110.002642. doi: 10.1074/mcp.M110.002642., Epub 2011 Jan 31. PMID:21282530 doi:10.1074/mcp.M110.002642
- ↑ Pelisch F, Pozzi B, Risso G, Munoz MJ, Srebrow A. DNA damage-induced heterogeneous nuclear ribonucleoprotein K sumoylation regulates p53 transcriptional activation. J Biol Chem. 2012 Aug 31;287(36):30789-99. doi: 10.1074/jbc.M112.390120. Epub, 2012 Jul 23. PMID:22825850 doi:http://dx.doi.org/10.1074/jbc.M112.390120
- ↑ Kagey MH, Melhuish TA, Wotton D. The polycomb protein Pc2 is a SUMO E3. Cell. 2003 Apr 4;113(1):127-37. PMID:12679040
- ↑ Long J, Zuo D, Park M. Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin. J Biol Chem. 2005 Oct 21;280(42):35477-89. Epub 2005 Aug 1. PMID:16061479 doi:http://dx.doi.org/M504477200
- ↑ Roscic A, Moller A, Calzado MA, Renner F, Wimmer VC, Gresko E, Ludi KS, Schmitz ML. Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2. Mol Cell. 2006 Oct 6;24(1):77-89. PMID:17018294 doi:http://dx.doi.org/S1097-2765(06)00563-6
- ↑ Vandamme J, Volkel P, Rosnoblet C, Le Faou P, Angrand PO. Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells. Mol Cell Proteomics. 2011 Apr;10(4):M110.002642. doi: 10.1074/mcp.M110.002642., Epub 2011 Jan 31. PMID:21282530 doi:10.1074/mcp.M110.002642
- ↑ Pelisch F, Pozzi B, Risso G, Munoz MJ, Srebrow A. DNA damage-induced heterogeneous nuclear ribonucleoprotein K sumoylation regulates p53 transcriptional activation. J Biol Chem. 2012 Aug 31;287(36):30789-99. doi: 10.1074/jbc.M112.390120. Epub, 2012 Jul 23. PMID:22825850 doi:http://dx.doi.org/10.1074/jbc.M112.390120
- ↑ Stuckey JI, Dickson BM, Cheng N, Liu Y, Norris JL, Cholensky SH, Tempel W, Qin S, Huber KG, Sagum C, Black K, Li F, Huang XP, Roth BL, Baughman BM, Senisterra G, Pattenden SG, Vedadi M, Brown PJ, Bedford MT, Min J, Arrowsmith CH, James LI, Frye SV. A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1. Nat Chem Biol. 2016 Mar;12(3):180-7. doi: 10.1038/nchembio.2007. Epub 2016 Jan, 25. PMID:26807715 doi:http://dx.doi.org/10.1038/nchembio.2007
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