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Related Experiment Video

Updated: Jan 13, 2026

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

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Characterization of BRCA1-Associated Protein-1 (BAP1) Aggregation Properties Induced by Cancer-Associated Mutations.

Li-Ching Hsiao1,2, Sarita Puri1,3, Manoj Kumar Sriramoju1

  • 1Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.

Chembiochem : a European Journal of Chemical Biology
|October 28, 2025
PubMed
Summary

Mutations in the BRCA1-associated protein-1 (BAP1) tumor suppressor cause protein aggregation, impairing its function. This study reveals a secondary nucleation-dominated aggregation model for BAP1 variants, explaining their role in cancer progression.

Keywords:
BRCA1‐associated protein‐1aggregation kineticscancer disease

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Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
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Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1

Published on: February 17, 2011

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • BRCA1-associated protein-1 (BAP1) is a crucial tumor suppressor regulating DNA transcription via deubiquitinase activity.
  • Cancer-associated missense mutations in the BAP1 ubiquitin C-terminal hydrolase (UCH) domain lead to protein destabilization and aggregation, implicated in malignancies like mesothelioma and uveal melanoma.

Purpose of the Study:

  • To investigate the aggregation mechanisms of destabilized BAP1-UCH variants (N78S, C91W, F81V, G128R).
  • To elucidate how specific BAP1 mutations contribute to cancer progression through protein aggregation and impaired nuclear function.

Main Methods:

  • Thioflavin T (ThT) binding assays were employed to monitor protein aggregation.
  • AmyloFit analysis was used to characterize the aggregation kinetics and mechanisms.

Main Results:

  • All investigated BAP1-UCH variants exhibited a secondary nucleation-dominated aggregation model.
  • These variants showed strong concentration dependence and significantly accelerated aggregation rates.
  • The observed aggregation may lead to impaired nuclear import and increased cytosolic retention of BAP1.

Conclusions:

  • Specific BAP1 mutations drive protein aggregation through a secondary nucleation pathway.
  • Protein aggregation compromises BAP1's tumor-suppressing functions by affecting its nuclear localization.
  • These findings offer critical insights into the molecular mechanisms underlying BAP1-driven cancers.