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The circadian oscillator comprises interconnected transcriptional and translational feedback loops, but also requires finely coordinated protein homeostasis including protein degradation and maturation. However, the mechanisms underlying the mammalian clock protein maturation is largely unknown. In this study, we demonstrate that necdin, one of the Prader-Willi syndrome (PWS)-causative genes, is highly expressed in the suprachiasmatic nuclei (SCN), the pacemaker of circadian clocks in mammals. Mice deficient in necdin show abnormal behaviors during an 8-hour advance jet-lag paradigm and disrupted clock gene expression in the liver. By using yeast two hybrid screening, we identified BMAL1, the core component of the circadian clock, and co-chaperone SGT1 as two necdin-interactive proteins. BMAL1 and SGT1 associated with the N-terminal and C-terminal fragments of necdin, respectively. Mechanistically, necdin enables SGT1-HSP90 chaperone machinery to stabilize BMAL1. Depletion of necdin or SGT1\/HSP90 leads to degradation of BMAL1 through the ubiquitin\u2013proteasome system, resulting in alterations in both clock gene expression and circadian rhythms. Taken together, our data identify the PWS-associated protein necdin as a novel regulator of the circadian clock, and further emphasize the critical roles of chaperone machinery in circadian clock regulation.<\/jats:p>","DOI":"10.1093\/nar\/gkaa601","type":"journal-article","created":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T11:13:09Z","timestamp":1594120389000},"page":"7944-7957","source":"Crossref","is-referenced-by-count":42,"title":["Necdin regulates BMAL1 stability and circadian clock through SGT1-HSP90 chaperone machinery"],"prefix":"10.1093","volume":"48","author":[{"given":"Renbin","family":"Lu","sequence":"first","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P. R. China"},{"name":"Hunan Key Laboratory of Animal Models for Human Diseases, Changsha 410078, Hunan, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufan","family":"Dong","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-3518","authenticated-orcid":false,"given":"Jia-Da","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, P. R. China"},{"name":"Hunan Key Laboratory of Animal Models for Human Diseases, Changsha 410078, Hunan, P. R. China"},{"name":"Hunan Key Laboratory of Medical Genetics, Changsha 410078, Hunan, P. R. 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