title: Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2.
abstract: Endogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving clock genes and their protein products. Post-translational modifications, including ubiquitination, are important for regulating the clock feedback mechanism. Previous work has focused on the role of ubiquitin ligases in the clock mechanism. Here we show a role for the rhythmically-expressed deubiquitinating enzyme ubiquitin specific peptidase 2 (USP2) in clock function. Mice with a deletion of the Usp2 gene (Usp2 KO) display a longer free-running period of locomotor activity rhythms and altered responses of the clock to light. This was associated with altered expression of clock genes in synchronized Usp2 KO mouse embryonic fibroblasts and increased levels of clock protein PERIOD1 (PER1). USP2 can be coimmunoprecipitated with several clock proteins but directly interacts specifically with PER1 and deubiquitinates it. Interestingly, this deubiquitination does not alter PER1 stability. Taken together, our results identify USP2 as a new core component of the clock machinery and demonstrate a role for deubiquitination in the regulation of the circadian clock, both at the level of the core pacemaker and its response to external cues.
authors.affiliation: Polypeptide Laboratory, Department of Medicine, McGill University and McGill University Health Centre Research Institute ,  Montréal, QC H3A 2B2 ,  Canada.
authors.forename: Yaoming
authors.initials: Y
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Duguay
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bédard
authors.forename: Adeline
authors.initials: A
authors.lastname: Rachalski
authors.forename: Gerardo
authors.initials: G
authors.lastname: Baquiran
authors.forename: Chan Hyun
authors.initials: CH
authors.lastname: Na
authors.forename: Jan
authors.initials: J
authors.lastname: Fahrenkrug
authors.forename: Kai-Florian
authors.initials: KF
authors.lastname: Storch
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Simon S
authors.initials: SS
authors.lastname: Wing
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cermakian