Abstract
The deubiquitinating enzyme BAP1 is an important tumor suppressor that has drawn attention in the clinic since its loss leads to a variety of cancers. BAP1 is activated by ASXL1 to deubiquitinate mono-ubiquitinated H2A at K119 in Polycomb gene repression, but the mechanism of this reaction remains poorly defined. Here we show that the BAP1 C-terminal extension is important for H2A deubiquitination by auto-recruiting BAP1 to nucleosomes in a process that does not require the nucleosome acidic patch. This initial encounter-like complex is unproductive and needs to be activated by the DEUBAD domains of ASXL1, ASXL2 or ASXL3 to increase BAP1's affinity for ubiquitin on H2A, to drive the deubiquitination reaction. The reaction is specific for Polycomb modifications of H2A as the complex cannot deubiquitinate the DNA damage-dependent ubiquitination at H2A K13/15. Our results contribute to the molecular understanding of this important tumor suppressor.
Highlights
The deubiquitinating enzyme BRCA-1-associated protein 1 (BAP1) is an important tumor suppressor that has drawn attention in the clinic since its loss leads to a variety of cancers
In this paper we describe that similar to the homologous UCH-L5/RPN13DEU complex, the DEUBAD domains of additional sexcombs like 1 (ASXL1), ASXL2 and ASXL3 can activate BAP1 by increasing BAP1’s affinity for the ubiquitin in the substrate, through a combination of mild effects
We observed that activation by ASXL proteins is not sufficient for deubiquitination of BAP1’s natural substrate histone 2A (H2A)
Summary
The deubiquitinating enzyme BAP1 is an important tumor suppressor that has drawn attention in the clinic since its loss leads to a variety of cancers. We show that the BAP1 C-terminal extension is important for H2A deubiquitination by auto-recruiting BAP1 to nucleosomes in a process that does not require the nucleosome acidic patch This initial encounter-like complex is unproductive and needs to be activated by the DEUBAD domains of ASXL1, ASXL2 or ASXL3 to increase BAP1’s affinity for ubiquitin on H2A, to drive the deubiquitination reaction. For BAP1 to deubiquitinate H2A, it requires activation by an N-terminal fragment of Polycomb group protein ASX, a protein necessary for the long-term repression of HOX genes[19]. This complex is highly conserved and deubiquitinates H2A in mammals[7,11,14]. ASXL1 is together with ASXL3 implicated in the Bohring–Opitz syndrome, a disorder characterized by malformation of the body and intellectual disability[24]
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