PAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution.

Autor: Asante Y; Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA., Benischke K; University Children's Hospital, Children's Research Center and Department of Oncology, Steinwiesstrasse 75, CH-8032, Zürich, Switzerland., Osman I; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Ngo QA; University Children's Hospital, Children's Research Center and Department of Oncology, Steinwiesstrasse 75, CH-8032, Zürich, Switzerland., Wurth J; University Children's Hospital, Children's Research Center and Department of Oncology, Steinwiesstrasse 75, CH-8032, Zürich, Switzerland., Laubscher D; University Children's Hospital, Children's Research Center and Department of Oncology, Steinwiesstrasse 75, CH-8032, Zürich, Switzerland., Kim H; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Udhayakumar B; Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA., Khan MIH; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Chin DH; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Porch J; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Chakraborty M; Axiotl Inc, Cleveland, OH, USA., Sallari R; Axiotl Inc, Cleveland, OH, USA., Delattre O; INSERM U830, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France., Zaidi S; INSERM U830, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France., Morice S; Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland., Surdez D; Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland., Danielli SG; University Children's Hospital, Children's Research Center and Department of Oncology, Steinwiesstrasse 75, CH-8032, Zürich, Switzerland., Schäfer BW; University Children's Hospital, Children's Research Center and Department of Oncology, Steinwiesstrasse 75, CH-8032, Zürich, Switzerland. beat.schaefer@kispi.uzh.ch., Gryder BE; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. berkley.gryder@case.edu., Wachtel M; University Children's Hospital, Children's Research Center and Department of Oncology, Steinwiesstrasse 75, CH-8032, Zürich, Switzerland. marco.wachtel@kispi.uzh.ch.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Dec 15; Vol. 14 (1), pp. 8361. Date of Electronic Publication: 2023 Dec 15.
DOI: 10.1038/s41467-023-43780-4
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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