Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response

Gorrepati, Kanaka Durga Devi; Lupse, Blaz; Annamalai, Karthika; Yuan, Ting; Maedler, Kathrin; Ardestani, Amin

Abstract

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

Citation

Gorrepati, K. D. D., Lupse, B., Annamalai, K., Yuan, T., Maedler, K., & Ardestani, A. (2018). Loss of Deubiquitinase USP1 Blocks Pancreatic β-Cell Apoptosis by Inhibiting DNA Damage Response. iScience, 1, 72-86. https://doi.org/10.1016/j.isci.2018.02.003

• Journal Article Type: Article
• Acceptance Date: Feb 1, 2018
• Online Publication Date: Mar 23, 2018
• Publication Date: Mar 23, 2018
• Deposit Date: Jan 4, 2024
• Publicly Available Date: Jan 8, 2024
• Journal: iScience
• Print ISSN: 2589-0042
• Electronic ISSN: 2589-0042
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 1
• Pages: 72-86
• DOI: https://doi.org/10.1016/j.isci.2018.02.003
• Keywords: Biochemical mechanism; Endocrinology; Cell biology
• Public URL: https://hull-repository.worktribe.com/output/4461643