Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response
Summary: Impaired pancreatic β-cell survival contributes to the reduced β-cell mass in diabetes, but underlying regulatory mechanisms and key players in this process remain incompletely understood. Here, we identified the deubiquitinase ubiquitin-specific protease 1 (USP1) as an important player in...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | iScience |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004218300075 |
| _version_ | 1818447703355424768 |
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| author | Kanaka Durga Devi Gorrepati Blaz Lupse Karthika Annamalai Ting Yuan Kathrin Maedler Amin Ardestani |
| author_facet | Kanaka Durga Devi Gorrepati Blaz Lupse Karthika Annamalai Ting Yuan Kathrin Maedler Amin Ardestani |
| author_sort | Kanaka Durga Devi Gorrepati |
| collection | DOAJ |
| description | Summary: Impaired pancreatic β-cell survival contributes to the reduced β-cell mass in diabetes, but underlying regulatory mechanisms and key players in this process remain incompletely understood. Here, we identified the deubiquitinase ubiquitin-specific protease 1 (USP1) as an important player in the regulation of β-cell apoptosis under diabetic conditions. Genetic silencing and pharmacological suppression of USP1 blocked β-cell death in several experimental models of diabetes in vitro and ex vivo without compromising insulin content and secretion and without impairing β-cell maturation/identity genes in human islets. Our further analyses showed that USP1 inhibition attenuated DNA damage response (DDR) signals, which were highly elevated in diabetic β-cells, suggesting a USP1-dependent regulation of DDR in stressed β-cells. Our findings highlight a novel function of USP1 in the control of β-cell survival, and its inhibition may have a potential therapeutic relevance for the suppression of β-cell death in diabetes. : Biochemical Mechanism; Endocrinology; Cell Biology Subject Areas: Biochemical Mechanism, Endocrinology, Cell Biology |
| first_indexed | 2024-12-14T20:07:50Z |
| format | Article |
| id | doaj.art-c4beac77065249e29a987b024a8b45f6 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-14T20:07:50Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-c4beac77065249e29a987b024a8b45f62022-12-21T22:48:59ZengElsevieriScience2589-00422018-03-0117286Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage ResponseKanaka Durga Devi Gorrepati0Blaz Lupse1Karthika Annamalai2Ting Yuan3Kathrin Maedler4Amin Ardestani5Islet Biology Laboratory, University of Bremen, Centre for Biomolecular Interactions Bremen, Leobener Straße NW2, Room B2080, 28359 Bremen, GermanyIslet Biology Laboratory, University of Bremen, Centre for Biomolecular Interactions Bremen, Leobener Straße NW2, Room B2080, 28359 Bremen, GermanyIslet Biology Laboratory, University of Bremen, Centre for Biomolecular Interactions Bremen, Leobener Straße NW2, Room B2080, 28359 Bremen, GermanyIslet Biology Laboratory, University of Bremen, Centre for Biomolecular Interactions Bremen, Leobener Straße NW2, Room B2080, 28359 Bremen, GermanyIslet Biology Laboratory, University of Bremen, Centre for Biomolecular Interactions Bremen, Leobener Straße NW2, Room B2080, 28359 Bremen, Germany; Corresponding authorIslet Biology Laboratory, University of Bremen, Centre for Biomolecular Interactions Bremen, Leobener Straße NW2, Room B2080, 28359 Bremen, Germany; Corresponding authorSummary: Impaired pancreatic β-cell survival contributes to the reduced β-cell mass in diabetes, but underlying regulatory mechanisms and key players in this process remain incompletely understood. Here, we identified the deubiquitinase ubiquitin-specific protease 1 (USP1) as an important player in the regulation of β-cell apoptosis under diabetic conditions. Genetic silencing and pharmacological suppression of USP1 blocked β-cell death in several experimental models of diabetes in vitro and ex vivo without compromising insulin content and secretion and without impairing β-cell maturation/identity genes in human islets. Our further analyses showed that USP1 inhibition attenuated DNA damage response (DDR) signals, which were highly elevated in diabetic β-cells, suggesting a USP1-dependent regulation of DDR in stressed β-cells. Our findings highlight a novel function of USP1 in the control of β-cell survival, and its inhibition may have a potential therapeutic relevance for the suppression of β-cell death in diabetes. : Biochemical Mechanism; Endocrinology; Cell Biology Subject Areas: Biochemical Mechanism, Endocrinology, Cell Biologyhttp://www.sciencedirect.com/science/article/pii/S2589004218300075 |
| spellingShingle | Kanaka Durga Devi Gorrepati Blaz Lupse Karthika Annamalai Ting Yuan Kathrin Maedler Amin Ardestani Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response iScience |
| title | Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response |
| title_full | Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response |
| title_fullStr | Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response |
| title_full_unstemmed | Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response |
| title_short | Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response |
| title_sort | loss of deubiquitinase usp1 blocks pancreatic β cell apoptosis by inhibiting dna damage response |
| url | http://www.sciencedirect.com/science/article/pii/S2589004218300075 |
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