Molecular Regulation of the Polycomb Repressive-Deubiquitinase

Our plain-English summary of Molecular Regulation of the Polycomb Repressive-Deubiquitinase, by C.J. Reddington, M. Fellner, A.E. Burgess, et al (International Journal of Molecular Sciences, 2020).

The study

• Authors: C.J. Reddington, M. Fellner, A.E. Burgess, P.D. Mace
• Journal: International Journal of Molecular Sciences
• Published: 2020;21(21)
• Type of article: Review
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article is a review, not an original study. The authors summarized research on the Polycomb Repressive-Deubiquitinase (PR-DUB). It removes a chemical tag called ubiquitin from the histone protein H2A, helping control which genes are switched on or off. They drew on structural studies of the fruit fly (Drosophila melanogaster) complex, biochemical studies of the human complex, and studies of proteins that bind to it. In humans, the complex's enzyme is BAP1. Citing earlier work, the authors described BAP1 tumour predisposition syndrome. It first came to light in families with increased rates of malignant mesothelioma despite minimal exposure to asbestos. They reported that about 85% of heterozygous carriers are diagnosed with cancer. A mutation database recorded somatic BAP1 mutations in 21% of pleural and 32% of eye cancers. They also wrote, citing a study in mice with one inherited altered copy of BAP1, that a single functional copy does not protect from the effects of asbestos exposure. The authors concluded that PR-DUB activity is regulated at multiple levels and that BAP1 mutations do not dictate disease progression alone.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of molecular, structural and biochemical research on the PR-DUB complex
• Who was studied: No study population. The review covers published structural studies of the Drosophila melanogaster PR-DUB, biochemical studies of the human PR-DUB, and functional studies of associated proteins.
• Exposure: No exposure was studied. Asbestos is mentioned only when describing earlier work: human families with BAP1 tumour predisposition syndrome, and a cited study of asbestos exposure in germline BAP1 heterozygous mice.
• Main results:
  • Citing earlier work, the review states that mesothelioma is normally tightly correlated to asbestos exposure.
  • Citing earlier studies, the review states that in BAP1 tumour predisposition syndrome, inactivating germline BAP1 mutations cause mesothelioma, melanoma and other neoplasms.
  • Citing an earlier study, the review reports that about 85% of heterozygous carriers of the syndrome are diagnosed with cancer.
  • Somatic BAP1 mutations occur most frequently in pleural cancers (21%) and eye cancers (32%), as annotated in the COSMIC database.
  • The review states that a single functional copy of BAP1 does not protect from the effects of asbestos exposure. The study it cites for this was in germline BAP1 heterozygous mice, not in people.
  • Citing earlier work, the review reports that loss of BAP1 does not induce apoptosis (cell death) in melanocytes or mesothelial cells.
  • A model proposed by Foglizzo et al. holds that pairing of two PR-DUB units increases binding to the nucleosome through a positively charged tail.
• The authors' conclusion: The authors concluded that PR-DUB activity is regulated at multiple levels, that a more comprehensive molecular model is needed to understand epigenetic protection against cancer, and that BAP1 mutations do not dictate disease progression alone.
• Limitations the authors state:
  • The authors state that relatively little is known about the interacting partners of the Drosophila PR-DUB, so parts of their account are speculative.
  • The authors state that a proposed association of ASXL proteins with PRC2 has not yet been confirmed in proteomic studies.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Carcinoma.

Related studies

• Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1 — S. Daou, H. Barbour, et al. (2018)
• Proteasomal degradation of polycomb-group protein CBX6 confers MMP-2 expression essential for mesothelioma invasion — K. Sakai, T. Nishiuchi, et al. (2020)
• Roles and mechanisms of BAP1 deubiquitinase in tumor suppression — L. Masclef, O. Ahmed, et al. (2021)
• Research progress on the regulation of mesothelioma driven by deubiquitinating enzyme BAP1 — W.T. Xuan, Y. Dong, et al. (2026)
• Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines — T. Mirzapoiazova, A. Pozhitkov, et al. (2020)
• Molecular characterization of diffuse malignant peritoneal mesothelioma — Y.P. Hung, F. Dong, et al. (2020)

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