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

IScience
Kanaka Durga Devi GorrepatiAmin Ardestani

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.

Citations

Mar 6, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Si-Wei WangFeng Zhang
Aug 16, 2021·The Journal of Biological Chemistry·Nathan A Snyder, Gustavo M Silva

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Methods Mentioned

BETA
environmental stress
ubiquitination
transfection
deubiquitination

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis