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However, the spatiotemporal dynamics of this feedback loop and the precise role of CK1\u03b4 remain incompletely understood. Using an inducible overexpression system, we show that nuclear availability of CK1\u03b4 is limited by both rapid nuclear degradation and active export of unassembled kinase, while cytoplasmic kinase is readily available for association with PERs. We demonstrate that CK1\u03b4-mediated phosphorylation may disrupt PER2\u2013CRY1 interaction, thereby resulting in cytoplasmic PER2 dimers containing substoichiometric amounts of CRY1. Analysis of endogenous PER2 localization in the context of an intact circadian clock reveals that PER2 accumulates in the cytoplasm late in the circadian cycle. Based on these findings, we propose that cytoplasmic accumulation of PER:CRY:CK1\u03b4 complexes contributes to the clearance of nuclear PER2, while the CK1\u03b4-dependent release of CRY1 into the nucleus may sustain CLOCK:BMAL1 repression on DNA, supporting the transition from the early to the late repressive phase.<\/jats:p>","DOI":"10.7554\/elife.110786","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T14:31:54Z","timestamp":1777645914000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.110786","source":"Crossref","is-referenced-by-count":3,"title":["Nuclear CK1\u03b4 as a critical determinant of PER:CRY complex dynamics and circadian period"],"prefix":"10.7554","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8906-9343","authenticated-orcid":true,"given":"Fidel Emmanuel","family":"Serrano","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/038t36y30","id-type":"ROR","asserted-by":"publisher"}],"name":"Heidelberg University Biochemistry Center","place":["Heidelberg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Daniela","family":"Marzoll","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/038t36y30","id-type":"ROR","asserted-by":"publisher"}],"name":"Heidelberg University Biochemistry Center","place":["Heidelberg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Bianca","family":"Ruppert","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/038t36y30","id-type":"ROR","asserted-by":"publisher"}],"name":"Heidelberg University Biochemistry Center","place":["Heidelberg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Axel CR","family":"Diernfellner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/038t36y30","id-type":"ROR","asserted-by":"publisher"}],"name":"Heidelberg University Biochemistry Center","place":["Heidelberg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9798-3047","authenticated-orcid":true,"given":"Michael","family":"Brunner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/038t36y30","id-type":"ROR","asserted-by":"publisher"}],"name":"Heidelberg University Biochemistry Center","place":["Heidelberg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.molcel.2017.07.017","type":"journal-article","article-title":"Macromolecular assemblies of the mammalian circadian clock","volume":"67","author":"Aryal","year":"2017","journal-title":"Molecular Cell"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1124\/jpet.107.122846","type":"journal-article","article-title":"An inhibitor of casein kinase I epsilon induces phase delays in circadian rhythms under free-running and entrained conditions","volume":"322","author":"Badura","year":"2007","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/s0896-6273(01)00302-6","type":"journal-article","article-title":"Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock","volume":"30","author":"Bae","year":"2001","journal-title":"Neuron"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/nrg1633","type":"journal-article","article-title":"Circadian rhythms from multiple oscillators: lessons from diverse organisms","volume":"6","author":"Bell-Pedersen","year":"2005","journal-title":"Nature Reviews. 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