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Single-Molecule Imaging of EWS-FLI1 Condensates Assembling on DNA
Published on: September 8, 2021
Assembly of a Notch transcriptional activation complex requires multimerization
Rodrigo Vasquez-Del Carpio1, Fred M Kaplan, Kelly L Weaver
1Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family of Surgery and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, Miami, FL 33136, USA.
Molecular and Cellular Biology
|January 20, 2011
Summary
Notch intracellular domain (N(ICD)) multimers are key precursors for forming the Notch transcriptional activation complex. This complex assembly is mediated by interactions with Skip and Mastermind proteins before CSL resolves it on DNA.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Biology
Background:
- Notch receptors regulate cell proliferation and differentiation via cell-to-cell interactions.
- Aberrant Notch signaling, characterized by deregulated nuclear Notch intracellular domain (N(ICD)), is implicated in cancers like T-cell acute lymphoblastic leukemia (T-ALL).
- Nuclear N(ICD) forms a transcriptional complex with Mastermind-like 1 and CSL to control gene expression, but its assembly mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism of Notch transcriptional activation complex assembly.
- To investigate the role of Notch intracellular domain (N(ICD)) multimerization in complex formation.
Main Methods:
- Investigated N(ICD) multimerization.
- Analyzed the interactions between N(ICD) multimers, Skip, Mastermind, and CSL.
- Characterized the stepwise assembly of the Notch activation complex.
Main Results:
- Demonstrated that N(ICD) multimerizes.
- Showed that N(ICD) multimers serve as precursors for the stepwise assembly of the Notch activation complex.
- Revealed that N(ICD) multimer-Skip-Mastermind interactions form a preactivation complex, which is subsequently resolved by CSL on DNA.
Conclusions:
- N(ICD) multimerization is a critical initial step in Notch transcriptional activation complex formation.
- The assembly pathway involves a preactivation complex mediated by N(ICD) multimers, Skip, and Mastermind.
- CSL plays a role in resolving the preactivation complex to establish the final DNA-bound Notch transcriptional activation complex.
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