A Chemical Probe For Tudor Domain Protein Spin1 to Investigate Chromatin Functions
Fagan V., Johansson C., Gileadi C., Monteiro O., Dunford J., Nibhani R., Philpott M., Malzahn J., Wells G., Farham R., Cribbs A., Halidi N., Li F., Chau I., Greschik H., Velupillai S., Hassani AA., Bennett J., Christott T., Giroud C., Lewis A., Huber K., Athanasou N., Bountra C., Jung M., Schüle R., Vedadi M., Arrowsmith C., Xiong Y., Jin J., Fedorov O., Farnie G., Brennan P., Oppermann U.
<div>Lysine and arginine methylation are amongst the most frequent modifications on unstructured histone tails and in</div><div>combination with other modifications provide the basis for a combinatorial 'chromatin or histone code'. Recognition of modified</div><div>histone residues is accomplished in a specific manner by 'reader' domains that recognize chromatin modifications, allowing for</div><div>association with specific effector complexes that mediate chromatin functions. The methyl-lysine and methyl-arginine reader domain</div><div>protein SPINDLIN1 (SPIN1) belongs to a family of 5 human genes, and has been identified as a putative oncogene and transcriptional</div><div>co-activator. It contains three Tudor domains that are able to mediate chromatin binding. Here we report on the discovery</div><div>of a potent and selective bidentate Tudor domain inhibitor, which simultaneously engages Tudor domains 1 and 2 and effectively</div><div>competes with chromatin binding in cells. Inhibitor, chemoproteomic and knockdown studies in squamous cell carcinoma indicate</div><div>complex SPIN-mediated chromatin interactions leading to transcriptional changes in cellular differentiation processes.</div>