Autodeubiquitination Protects the Tumor Suppressor BAP1 from Cytoplasmic Sequestration Mediated by the Atypical Ubiquitin Ligase UBE2O

Abstract

The tumor suppressor BAP1 interacts with chromatin-associated proteins and regulates cell proliferation, but its mechanism of action and regulation remain poorly defined. We show that the ubiquitin-conjugating enzyme UBE2O multi-monoubiquitinates the nuclear localization signal of BAP1, thereby inducing its cytoplasmic sequestration. This activity is counteracted by BAP1 autodeubiquitination through intramolecular interactions. Significantly, we identified cancer-derived BAP1 mutations that abrogate autodeubiquitination and promote its cytoplasmic retention, indicating that BAP1 autodeubiquitination ensures tumor suppression. The antagonistic relationship between UBE2O and BAP1 is also observed during adipogenesis, whereby UBE2O promotes differentiation and cytoplasmic localization of BAP1. Finally, we established a putative targeting consensus sequence of UBE2O and identified numerous chromatin remodeling factors as potential targets, several of which tested positive for UBE2O-mediated ubiquitination. Thus, UBE2O defines an atypical ubiquitin-signaling pathway that coordinates the function of BAP1 and establishes a paradigm for regulation of nuclear trafficking of chromatin-associated proteins.

Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis

“…It will be interesting to investigate the potential impact of this BAP1 modification on the increase of Ino80 after HU treatment. In keeping with our finding of BAP1 activity in the regulation of Ino80, it has recently been reported that the ubiquitin-conjugating enzyme UBE2O sequesters BAP1 in the cytoplasm by ubiquitinating its nuclear localization signal, resulting in an increase in Ino80 ubiquitination and a decrease in the Ino80 level 50 .…”

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…BAP1 could be modified by post-translational modifications inhibiting its autodeubiquitination activity that lead to a cytoplasmic sequestration of BAP1 mediated by regulatory proteins, without any export signal in BAP1 gene. As a matter of fact, several ubiquitination sites of BAP1 were identified in vitro study by Mashtalir and coworkers [38].…”

“…occur in about 5% of all tumors (COSMIC; http://cancer.sanger.ac.uk/cosmic) and in 6% considering sporadic MM, only [38]. This novel BAP1 alteration leads to a probably impaired deubiquitinase activity of BAP1 protein, suggesting its pathogenic role.…”

The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

“…BAP1 is also recruited to sites of DNA double strand breaks to promote repair by homologous recombination (24,28), and it is implicated in DNA replication-associated processes (29,30). Moreover, BAP1 functions appear to be regulated by posttranslational modifications, including phosphorylation and ubiquitination (24,30,31). Nonetheless, the mechanism by which BAP1 function is coordinated by its partners remains poorly defined.…”