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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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CRISPR Screen Identifies BAP1 as a Deubiquitinase Regulating SPIN4 Stability.
Alondra Sanchez1, Chen Zhou1, Rima Tulaiha2,3
1Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
Biochemistry
|September 30, 2025
Summary
The deubiquitinase BAP1 stabilizes Spindlin-4 (SPIN4) by removing ubiquitin tags, maintaining protein homeostasis. Loss of BAP1 reduces SPIN4 levels, impacting epigenetic regulation and disease.
Area of Science:
- Molecular Biology
- Epigenetics
- Ubiquitin Biology
Background:
- Protein homeostasis is regulated by E3 ubiquitin ligases and deubiquitinases (DUBs).
- Spindlin-4 (SPIN4), a histone H3K4me3 reader, was previously identified as a degradation substrate of DCAF16.
Purpose of the Study:
- To investigate the regulatory mechanisms controlling SPIN4 stability.
- To identify the deubiquitinase responsible for SPIN4 homeostasis.
Main Methods:
- E3 ligase-focused CRISPR-Cas9 knockout screen.
- Deubiquitinase-focused CRISPR-Cas9 knockout screen.
- Biochemical analyses, proteomics, and interactome studies.
Main Results:
- Confirmed SPIN4 as a degradation substrate of DCAF16.
- Identified BAP1 as a deubiquitinase that interacts with and stabilizes SPIN4.
- Demonstrated that BAP1 deubiquitination activity is essential for maintaining SPIN4 levels.
Conclusions:
- BAP1 plays a critical role in maintaining SPIN4 homeostasis through deubiquitination.
- This regulatory axis highlights a dynamic balance controlling SPIN4 stability.
- Findings have implications for understanding epigenetic regulation and disease processes.
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