Abstract
H2Bub1 DUBs compete for binding to the adaptor proteins ATXN7L3 and ENY2 that facilitate DUB activity.
Major finding: H2Bub1 DUBs compete for binding to the adaptor proteins ATXN7L3 and ENY2 that facilitate DUB activity.
Concept: The DUBs USP27X and USP51 act independently of the SAGA complex to deubiquitinate histone H2B.
Impact: Disruption of the balance of the DUBs regulated by ATXN7L3 and ENY2 may promote tumor progression.
Monoubiquitination of histone H2B (H2Bub1) is critical in the regulation of gene activity. H2Bub1 levels are regulated by the deubiquitination module (DUBm) of the SAGA complex, which contains the USP22 deubiquitinating enzyme (DUB), and is closely associated with two adaptor proteins, ATXN7L3 and ENY2. Dysregulated histone ubiquitination has been linked to cancer, and USP22 overexpression is associated with poor outcomes in multiple tumor types. However, the mechanisms that link USP22 overexpression and histone deubiquitination to cancer are not understood. Atanassov and colleagues generated cell lines with each of the DUBm proteins depleted, including USP22, ATXN7L3, and ENY2. Analysis of H2Bub1 in these cells revealed that the loss of ATXN7L3 or ENY2 led to elevated H2Bub1, whereas USP22 depletion led to a slight reduction in H2Bub1, indicating that the adaptor proteins had a greater effect on H2B deubiquitination than the catalytic USP22 subunit. Correspondingly, ATXN7L3 and ENY2 were found to interact with two other H2Bub1 DUBs that were not components of the SAGA complex, USP27X and USP51, and to be required for their DUB activity. USP27X, USP51, and USP22 were shown to compete for binding to ATXN7L3 and ENY2. Depletion of USP22, USP27X, or USP51 led to a subtle reduction of global H2Bub1, likely because depletion would leave more ATXN7L3 and ENY2 available to bind to remaining USPs. Depletion of USP27X or USP51 impaired breast cancer cell proliferation, and depletion of USP27X in a mouse xenograft model reduced tumor size. Further, data from The Cancer Genome Atlas showed that increased expression of ENY2 and ATXN7L3 is associated with increased incidence of breast cancer due to loss of DUB activity. Likewise, USP22 overexpression may promote tumorigenesis by altering ENY2 and AXN7L3 availability. Altogether, these data reveal that ATXN7L3 and ENY2 facilitate the activity of multiple deubiquitinating enzymes and suggest that imbalanced USP activity may enhance tumorigenesis.