Abstract
Post-translational modification of histone proteins plays a major role in histone–DNA packaging and ultimately gene expression. Attachment of ubiquitin to the C-terminal tail of histone H2A (H2AK119Ub in mammals) is particularly relevant to the repression of gene transcription, and is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here, we outline recent advances in the understanding of PR-DUB regulation, which have come through structural studies of the Drosophila melanogaster PR-DUB, biochemical investigation of the human PR-DUB, and functional studies of proteins that associate with the PR-DUB. In humans, mutations in components of the PR-DUB frequently give rise to malignant mesothelioma, melanomas, and renal cell carcinoma, and increase disease risk from carcinogens. Diverse mechanisms may underlie disruption of the PR-DUB across this spectrum of disease. Comparing and contrasting the PR-DUB in mammals and Drosophila reiterates the importance of H2AK119Ub through evolution, provides clues as to how the PR-DUB is dysregulated in disease, and may enable new treatment approaches in cancers where the PR-DUB is disrupted.
Highlights
Cells face the fundamental challenge of storing a vast genome in limited three-dimensional space, while allowing for orderly access to DNA
Comparing and contrasting the Polycomb Repressive-Deubiquitinase (PR-DUB) in mammals and Drosophila reiterates the importance of H2AK119Ub through evolution, provides clues as to how the PR-DUB is dysregulated in disease, and may enable new treatment approaches in cancers where the PR-DUB is disrupted
The activity of the PR-DUB deubiquitinase is regulated at multiple levels, namely by assembly of a tight complex between BAP1 or Calypso and an Additional sex combs (Asx)-like protein, a 2:2 “double-heterodimer” complex likely to only occur upon localised enrichment in specific regions of chromatin [8], and interactions with a range of cellular binding partners likely to modulate specificity and function
Summary
Cells face the fundamental challenge of storing a vast genome in limited three-dimensional space, while allowing for orderly access to DNA. The incidence of oncogenic mutations in the genes encoding components of the protein complexes that write and erase ubiquitin histone marks has focused interest on their regulation and on how the process as a whole is integrated with other histone modifications. Two proteins in Drosophila, Calypso and Additional sex combs (Asx), form the PR-DUB complex. Proteins in Drosophila, Calypso and Additional sexwhich combshydrolyses (Asx), formH2AUb the PR-DUB complex. Calypso is the catalytic deubiquitinase within the complex, which hydrolyses H2AUb when activated by Asx [6] (Figure 1). A single homolog of Calypso exists (BRCA1-associated protein 1; by Asx [6] (Figure 1). A single homolog of Calypso exists (BRCA1-associated protein 1; BAP1), which can be activated by one of three Asx-like (ASXL) proteins (ASXL1–3). HB1, ASXL, endonuclease helix-turn-helix (HARE-HTH) domain at their N-terminus, which is noticeably absent from Asx [14] (Figure 1)
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