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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR.
Sinem Usluer1, Emil Spreitzer1, Benjamin Bourgeois1
1Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Department of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
International Journal of Molecular Sciences
|November 13, 2021
Summary
The C9orf72 gene mutation causes ALS and FTD. This study reveals that the tumor suppressor p53 interacts with toxic repeats, promoting neurodegeneration. Reducing p53 levels may offer a therapeutic strategy for these devastating diseases.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The C9orf72 gene mutation is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Poly-PR/GR dipeptide repeats from C9orf72 alter chromatin accessibility, stabilizing and enhancing the tumor suppressor p53's activity.
- Reduced p53 levels demonstrate neuroprotective effects against poly-PR/GR toxicity in cellular and model organism studies.
Purpose of the Study:
- To elucidate the detailed molecular mechanisms by which p53 contributes to poly-PR/GR-mediated neurodegeneration.
- To investigate the physical interaction between p53 and poly-PR/GR repeats.
- To identify the specific domains and interaction types involved in p53-poly-PR/GR binding.
Main Methods:
- Nuclear magnetic resonance (NMR) spectroscopy
- Fluorescence polarization assays
- Turbidity assays
- Differential interference contrast (DIC) microscopy
Main Results:
- p53 physically interacts with poly-PR/GR repeats.
- This interaction triggers liquid-liquid phase separation of p53.
- The transactivation domain 2 (TAD2) of p53 is the primary binding site for poly-PR/GR.
- Binding is mediated by electrostatic and/or hydrophobic interactions.
Conclusions:
- p53 plays a mechanistic role in poly-PR/GR-associated neurodegeneration.
- Understanding the p53-poly-PR/GR interaction provides insights into C9orf72-linked diseases.
- Targeting the p53 interaction with poly-PR/GR could be a therapeutic avenue for ALS and FTD.
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