1. PAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution
- Author
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Asante, Yaw; https://orcid.org/0000-0002-6924-8632, Benischke, Katharina, Osman, Issra; https://orcid.org/0000-0001-5918-4543, Ngo, Quy A, Wurth, Jakob; https://orcid.org/0000-0002-1328-7122, Laubscher, Dominik, Kim, Hyunmin; https://orcid.org/0000-0003-0835-5044, Udhayakumar, Bhavatharini, Khan, Md Imdadul H; https://orcid.org/0000-0001-8002-5600, Chin, Diana H; https://orcid.org/0000-0002-1645-3552, Porch, Jadon, Chakraborty, Maharshi, Sallari, Richard, Delattre, Olivier; https://orcid.org/0000-0002-8730-2276, Zaidi, Sakina; https://orcid.org/0000-0001-9128-0287, Morice, Sarah, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Danielli, Sara G; https://orcid.org/0000-0003-3101-3114, Schäfer, Beat W; https://orcid.org/0000-0001-5988-2915, Gryder, Berkley E; https://orcid.org/0000-0003-0130-2302, Wachtel, Marco; https://orcid.org/0000-0002-6077-3692, Asante, Yaw; https://orcid.org/0000-0002-6924-8632, Benischke, Katharina, Osman, Issra; https://orcid.org/0000-0001-5918-4543, Ngo, Quy A, Wurth, Jakob; https://orcid.org/0000-0002-1328-7122, Laubscher, Dominik, Kim, Hyunmin; https://orcid.org/0000-0003-0835-5044, Udhayakumar, Bhavatharini, Khan, Md Imdadul H; https://orcid.org/0000-0001-8002-5600, Chin, Diana H; https://orcid.org/0000-0002-1645-3552, Porch, Jadon, Chakraborty, Maharshi, Sallari, Richard, Delattre, Olivier; https://orcid.org/0000-0002-8730-2276, Zaidi, Sakina; https://orcid.org/0000-0001-9128-0287, Morice, Sarah, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Danielli, Sara G; https://orcid.org/0000-0003-3101-3114, Schäfer, Beat W; https://orcid.org/0000-0001-5988-2915, Gryder, Berkley E; https://orcid.org/0000-0003-0130-2302, and Wachtel, Marco; https://orcid.org/0000-0002-6077-3692
- Abstract
Activation of oncogenic gene expression from long-range enhancers is initiated by the assembly of DNA-binding transcription factors (TF), leading to recruitment of co-activators such as CBP/p300 to modify the local genomic context and facilitate RNA-Polymerase 2 (Pol2) binding. Yet, most TF-to-coactivator recruitment relationships remain unmapped. Here, studying the oncogenic fusion TF PAX3-FOXO1 (P3F) from alveolar rhabdomyosarcoma (aRMS), we show that a single cysteine in the activation domain (AD) of P3F is important for a small alpha helical coil that recruits CBP/p300 to chromatin. P3F driven transcription requires both this single cysteine and CBP/p300. Mutants of the cysteine reduce aRMS cell proliferation and induce cellular differentiation. Furthermore, we discover a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription.
- Published
- 2023