Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1

• Published in: Science (American Association for the Advancement of Science) 2019-04, Vol.364 (6437), p.283-285
• Main Authors: He, Meng, Chaurushiya, Mira S, Webster, Joshua D, Kummerfeld, Sarah, Reja, Rohit, Chaudhuri, Subhra, Chen, Ying-Jiun, Modrusan, Zora, Haley, Benjamin, Dugger, Debra L, Eastham-Anderson, Jeffrey, Lau, Shari, Dey, Anwesha, Caothien, Roger, Roose-Girma, Merone, Newton, Kim, Dixit, Vishva M
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Cancer; Carcinogenesis - genetics; Cell death; Deactivation; Embryo cells; Embryo fibroblasts; Fibroblasts; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knock-In Techniques; Gene regulation; Gene silencing; Genes; Germ-Line Mutation; Hepatocytes; Histone H2A; Histones; Humans; Inactivation; Liver; Mcl-1 protein; Melanocytes; Melanocytes - metabolism; Melanocytes - pathology; Melanoma - genetics; Melanoma - pathology; Mesothelioma - genetics; Mesothelioma - pathology; Mice; Mice, Mutant Strains; Microphthalmia-associated transcription factor; Mutation; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Pancreas; Polycomb Repressive Complex 1 - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Selectivity; Stem cell transplantation; Stem cells; Suppressors; Tissues; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumorigenesis; Tumors; Ubiquitin; Ubiquitin Thiolesterase - genetics; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Uveal Neoplasms - genetics; Uveal Neoplasms - pathology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aav4902

Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example, encodes a widely expressed deubiquitinase for histone H2A, but germline mutations are predominantly associated with uveal melanomas and mesotheliomas. We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells. Ubiquitin ligase RNF2, which silences genes by monoubiquitinating H2A, promoted apoptosis in BAP1-deficient cells by suppressing expression of the prosurvival genes and In contrast, BAP1 loss in melanocytes had little impact on expression of prosurvival genes, instead inducing Thus, BAP1 appears to modulate gene expression by countering H2A ubiquitination, but its loss only promotes tumorigenesis in cells that do not engage an RNF2-dependent apoptotic program.