BAP1 as a guardian of genome stability: implications in human cancer

Our plain-English summary of BAP1 as a guardian of genome stability: implications in human cancer, by J. Kwon, D. Lee, S.A. Lee (Experimental & Molecular Medicine, 2023).

The study

• Authors: J. Kwon, D. Lee, S.A. Lee
• Journal: Experimental & Molecular Medicine
• Published: 2023;55(4):745-754
• Type of article: Review
• Cited by: 56 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BAP1 is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase with a wide array of biological activities. Studies in which advanced sequencing technologies were used have uncovered a link between BAP1 and human cancer. Somatic and germline mutations of the BAP1 gene have been identified in multiple human cancers, with a particularly high frequency in mesothelioma, uveal melanoma and clear cell renal cell carcinoma. BAP1 cancer syndrome highlights that all carriers of inherited BAP1-inactivating mutations develop at least one and often multiple cancers with high penetrance during their lifetime. These findings, together with substantial evidence indicating the involvement of BAP1 in many cancer-related biological activities, strongly suggest that BAP1 functions as a tumor suppressor. Nonetheless, the mechanisms that account for the tumor suppressor function of BAP1 have only begun to be elucidated. Recently, the roles of BAP1 in genome stability and apoptosis have drawn considerable attention, and they are compelling candidates for key mechanistic factors. In this review, we focus on genome stability and summarize the details of the cellular and molecular functions of BAP1 in DNA repair and replication, which are crucial for genome integrity, and discuss the implications for BAP1-associated cancer and relevant therapeutic strategies. We also highlight some unresolved issues and potential future research directions.

© 2023. The Author(s).

In plain English

This article was a review, not a new study. The authors summarized published research on BAP1, a gene mutated in several cancers including mesothelioma. They focused on how BAP1 helps keep DNA stable, describing earlier studies mostly in cultured cells. These reported that losing BAP1 reduced repair-protein gathering at broken DNA, impaired repair of ultraviolet-light damage, and affected DNA copying through a partner protein, INO80. The authors wrote that chromosome instability linked to BAP1 loss is clearly found in malignant mesothelioma. They added it was unclear whether some chromosome changes in mesothelioma tumors were caused by BAP1 loss. The review did not study asbestos; its introduction cited other work on it. Those reports said that, for mesothelioma, incidence in carriers of inherited BAP1 mutations increases with asbestos exposure; the authors called this an example of how genes and environment influence cancer risk. Mice carrying one faulty BAP1 copy were predisposed to malignant mesothelioma after asbestos exposure. Clinical studies did not show that PARP-inhibitor drugs selectively targeted BAP1-deficient mesothelioma cells. The authors proposed that BAP1 protects against cancer through both genome stability and apoptosis (cell death).

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 published laboratory and clinical studies on the role of BAP1 in DNA repair, DNA replication and genome stability
• Who was studied: no new population was studied; the review covered published studies, mostly in cultured cells (human, mouse and chicken cell lines), plus some mouse and clinical studies
• Exposure: The review did not study asbestos exposure. In its introduction it cited other studies reporting that, in the case of mesothelioma, cancer incidence in carriers of germline BAP1 mutations increases upon asbestos exposure, which the authors described as an example for studying how gene-environment interactions influence cancer risk. It also cited studies in which mice with heterozygous germline BAP1 mutations were predisposed to malignant mesothelioma after asbestos exposure. Fiber type was not specified.
• Main results:
  • A reviewed study found that depleting BAP1 in cells reduced the formation of foci of the double-strand-break repair proteins RAD51 and BRCA1.
  • A reviewed study found that BAP1 depletion in HEK 293 T cells led to defective repair of UV-induced DNA damage (CPDs) and increased UV sensitivity.
  • A reviewed study found that BAP1 deubiquitinated and stabilized INO80, a protein involved in DNA replication.
  • The authors stated that the link between BAP1 loss and chromosome instability is clearly found in malignant mesothelioma. For chromothripsis seen in mesothelioma tumor samples, they said it was unclear whether it was caused by BAP1 deletion.
  • Reviewed recent clinical studies indicated that PARP inhibition did not selectively target BAP1-deficient mesothelioma cells.
• The authors' conclusion: The authors proposed that BAP1 protects against cancer at two levels, through its roles in genome stability and in apoptosis.
• Limitations the authors state:
  • The authors stated that how BAP1 promotes repair of double-strand breaks and UV-induced lesions is largely unknown.
  • The authors stated that further studies are required before PARP inhibition can be applied as a treatment for BAP1-related cancers.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, Mesothelioma, Carcinoma, BAP1 Tumor Predisposition Syndrome, Apoptosis.

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• Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome — F. Lalloo, A. Kulkarni, et al. (2023)
• Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist — L.M. Martorano, R.R. Winkelmann, et al. (2014)
• Non-SMC condensin I complex subunit D2 (NCAPD2) reveals its prognostic and immunologic features in human cancers — X. Dong, T. Liu, et al. (2023)
• Clinical Implications of Real-time Integrative Sequencing in Management of Patients With Suspected Germline BAP1 Mutations — S. Sengupta, A.C. Weyand, et al. (2019)
• Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism — F. Gemignani, M. Neri, et al. (2009)

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