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

Impaired pancreatic beta-cell survival contributes to the reduced beta-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 beta-cell apoptosis under diabetic conditions. Genetic silencing and pharmacological suppression of USP1 blocked beta-cell death in several experimental models of diabetes in vitro and ex vivo without compromising insulin content and secretion and without impairing beta-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 beta-cells, suggesting a USP1-dependent regulation of DDR in stressed beta-cells. Our findings highlight a novel function of USP1 in the control of beta-cell survival, and its inhibition may have a potential therapeutic relevance for the suppression of beta-cell death in diabetes.