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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
Published on: July 25, 2019
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A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes
Martina Foglizzo1, Adam J Middleton1, Abigail E Burgess1
1Biochemistry Department, School of Biomedical Sciences, University of Otago, P.O. Box 56, 710, Cumberland St., Dunedin, 9054, New Zealand.
Nature Communications
|September 28, 2018
Summary
Polycomb Repressive-Deubiquitinase (PR-DUB) complexes remove the H2AK119Ub epigenetic mark. Structural studies reveal PR-DUB bidentate complex formation is crucial for chromatin recruitment and gene repression, impacting tumorigenesis.
Area of Science:
- Epigenetics
- Structural Biology
- Molecular Biology
Background:
- Histone 2A lysine 119 ubiquitination (H2AK119Ub) marks repressed genes.
- The Polycomb Repressive-Deubiquitinase (PR-DUB) complex removes this mark.
- Understanding PR-DUB structure is key to its function.
Purpose of the Study:
- Determine the crystal structure of the Drosophila PR-DUB complex.
- Elucidate the mechanism of H2AK119Ub removal by PR-DUB.
- Investigate the role of PR-DUB complex assembly in gene regulation and disease.
Main Methods:
- X-ray crystallography to determine PR-DUB structure.
- Biochemical assays to assess deubiquitinase activity.
- Mutagenesis studies to probe protein-protein interactions and function.
Main Results:
- The Drosophila PR-DUB complex forms a 2:2 Calypso-ASX heterotetramer.
- Complex formation relies on Calypso dimerization via coiled-coil regions.
- Disrupting the dimer interface impairs H2AK119Ub removal from nucleosomes.
- Human BAP1 mutations homologous to Calypso interfaces also affect nucleosome activity.
Conclusions:
- Bidentate PR-DUB complex assembly, driven by high local concentrations, is essential for efficient chromatin recruitment and H2AK119Ub removal.
- This mechanism provides a basis for PR-DUB's targeted activity on chromatin.
- PR-DUB mutations impacting complex formation are linked to tumorigenesis.
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