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

Yaw Asante, Katharina Benischke, Issra Osman, Quy A. Ngo, Jakob Wurth, Dominik Laubscher, Hyunmin Kim, Bhavatharini Udhayakumar, Md Imdadul H. Khan, Diana H. Chin, Jadon Porch, Maharshi Chakraborty, Richard Sallari, Olivier Delattre, Sakina Zaidi, Sarah Morice, Didier Surdez, Sara G. Danielli, Beat W. Schäfer (), Berkley E. Gryder () and Marco Wachtel ()
Additional contact information
Yaw Asante: Case Western Reserve University
Katharina Benischke: University Children’s Hospital, Children’s Research Center and Department of Oncology
Issra Osman: Case Western Reserve University
Quy A. Ngo: University Children’s Hospital, Children’s Research Center and Department of Oncology
Jakob Wurth: University Children’s Hospital, Children’s Research Center and Department of Oncology
Dominik Laubscher: University Children’s Hospital, Children’s Research Center and Department of Oncology
Hyunmin Kim: Case Western Reserve University
Bhavatharini Udhayakumar: Case Western Reserve University
Md Imdadul H. Khan: Case Western Reserve University
Diana H. Chin: Case Western Reserve University
Jadon Porch: Case Western Reserve University
Maharshi Chakraborty: Axiotl Inc
Richard Sallari: Axiotl Inc
Olivier Delattre: Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center
Sakina Zaidi: Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center
Sarah Morice: University of Zurich (UZH)
Didier Surdez: University of Zurich (UZH)
Sara G. Danielli: University Children’s Hospital, Children’s Research Center and Department of Oncology
Beat W. Schäfer: University Children’s Hospital, Children’s Research Center and Department of Oncology
Berkley E. Gryder: Case Western Reserve University
Marco Wachtel: University Children’s Hospital, Children’s Research Center and Department of Oncology

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
References: View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43780-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43780-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43780-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().