Circadian clocks are timing devices that rhythmically adjust organism's behavior, physiology, and metabolism to the 24-h day-night cycle. Eukaryotic circadian clocks rely on several interlocked transcription-translation feedback loops, where protein stability is the key part of the delay between transcription and the appearance of the mature proteins within the feedback loops. In bilaterian animals, including mammals and insects, the circadian clock depends on a homologous set of proteins. Despite mostly conserved clock components among the fruit fly Drosophila and mammals, several lineage-specific differences exist. Here we have systematically explored the evolution and sequence variability of insect DBT proteins and their vertebrate homologs casein kinase 1 delta (CKIδ) and epsilon (CKIε), dated the origin and separation of CKIδ from CKIε, and identified at least three additional independent duplications of the CKIδ/ε gene in Petromyzon, Danio, and Xenopus. We determined conserved regions in DBT specific to Diptera, and functionally tested a subset of those in D. melanogaster. Replacement of Lysine K224 with acidic residues strongly impacts the free-running period even in heterozygous flies, whereas homozygous mutants are not viable. K224D mutants have a temperature compensation defect with longer free-running periods at higher temperatures, which is exactly the opposite trend of what was reported for corresponding mammalian mutants. All DBTs of dipteran insects contain the NKRQK motif at positions 220-224. The occurrence of this motif perfectly correlates with the presence of BRIDE OF DOUBLETIME, BDBT, in Diptera. BDBT is a non-canonical FK506-binding protein that physically interacts with Drosophila DBT. The phylogeny of FK506-binding proteins suggests that BDBT is either absent or highly modified in non-dipteran insects. In addition to in silico analysis of DBT/CKIδ/ε evolution and diversity, we have identified four novel casein kinase 1 genes specific to the Drosophila genus.

Biology Center of the Academy of Sciences of the Czech Republic Institute of Entomology Ceske Budejovice Czechia

Faculty of Science University of South Bohemia Ceske Budejovice Czechia

Institute of Neuro and Behavioral Biology Westfälische Wilhelms University Münster Germany

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Agrawal P., Hardin P. E. (2016). An RNAi screen to identify protein phosphatases that function within the Drosophila circadian clock. G3 6, 4227–4238. 10.1534/g3.116.035345 PubMed DOI PMC

Arrhenius S. (1889). Über die Reaktionsgeschwindigkeit bei der Inversion von Rohrzucker durch Säuren. Zeitschrit fuer Phys. Chem. 4, 226–248. 10.1515/zpch-1889-0416 DOI

Aryal R. P., Kwak P. B., Tamayo A. G., Gebert M., Chiu P. L., Walz T., et al. (2017). Macromolecular assemblies of the mammalian circadian clock. Mol. Cell 67, 770–782. 10.1016/j.molcel.2017.07.017 PubMed DOI PMC

Ashmore L. J., Sathyanarayanan S., Silvestre D. W., Emerson M. M., Schotland P., Sehgal A. (2003). Novel insights into the regulation of the timeless protein. J. Neurosci. 23, 7810–7819. 10.1523/jneurosci.23-21-07810.2003 PubMed DOI PMC

Bajgar A., Jindra M., Dolezel D. (2013). Autonomous regulation of the insect gut by circadian genes acting downstream of juvenile hormone signaling. Proc. Natl. Acad. Sci. U. S. A. 110, 4416–4421. 10.1073/pnas.1217060110 PubMed DOI PMC

Bazalova O., Dolezel D. (2017). Daily activity of the housefly, Musca domestica, is influenced by temperature independent of 3’ UTR period gene splicing. G3 7, 2637–2649. 10.1534/g3.117.042374 PubMed DOI PMC

Ceriani M. F., Darlington T. K., Staknis D., Mas P., Petti A. A., Weitz C. J., et al. (1999). Light-dependent sequestration of TIMELESS by CRYPTOCHROME. Science 285, 553–556. 10.1126/science.285.5427.553 PubMed DOI

Chiu J. C., Ko H. W., Edery I. (2011). NEMO/NLK Phosphorylates PERIOD to initiate a time delay phosphorylation circuit that sets circadian clock speed. Cell 145, 357–370. 10.1016/j.cell.2011.04.002 PubMed DOI PMC

Chiu J. C., Vanselow J. T., Kramer A., Edery I. (2008). The phospho-occupancy of an atypical SLIMB-binding site on PERIOD that is phosphorylated by DOUBLETIME controls the pace of the clock. Genes Dev. 22, 1758–1772. 10.1101/gad.1682708 PubMed DOI PMC

Crosby P., Partch C. L. (2020). New insights into non-transcriptional regulation of mammalian core clock proteins. J. Cell Sci. 133, jcs241174. 10.1242/jcs.241174 PubMed DOI PMC

Cullati S. N., Chaikuad A., Chen J. S., Gebel J., Tesmer L., Zhubi R., et al. (2022). Kinase domain autophosphorylation rewires the activity and substrate specificity of CK1 enzymes. Mol. Cell 82, 2006–2020.e8. 10.1016/j.molcel.2022.03.005 PubMed DOI PMC

Dahlberg C. L., Nguyen E. Z., Goodlett D., Kimelman D. (2009). Interactions between Casein kinase Iepsilon (CKIepsilon) and two substrates from disparate signaling pathways reveal mechanisms for substrate-kinase specificity. PLoS One 4 (3), e4766. 10.1371/journal.pone.0004766 PubMed DOI PMC

Darlington T. K., Wager-Smith K., Ceriani M. F., Staknis D., Gekakis N., Steeves T. D. L., et al. (1998). Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280, 1599–1603. 10.1126/science.280.5369.1599 PubMed DOI

Dolezelova E., Dolezel D., Hall J. C. (2007). Rhythm defects caused by newly engineered null mutations in Drosophila’s cryptochrome gene. Genetics 177, 329–345. 10.1534/genetics.107.076513 PubMed DOI PMC

Dunlap J. C. (1999). Molecular bases for circadian clocks. Cell 96, 271–290. 10.1016/s0092-8674(00)80566-8 PubMed DOI

Emery P., Stanewsky R., Helfrich-Forster C., Emery-Le M., Hall J. C., Rosbash M. (2000). Drosophila CRY is a deep brain circadian photoreceptor. Neuron 26, 493–504. 10.1016/S0896-6273(00)81181-2 PubMed DOI

Fan J. Y., Agyekum B., Venkatesan A., Hall D. R., Keightley A., Bjes E. S., et al. (2013). Noncanonical FK506-binding protein BDBT binds DBT to enhance its circadian function and forms foci at night. Neuron 80, 984–996. 10.1016/j.neuron.2013.08.004 PubMed DOI PMC

Fan J. Y., Means J. C., Bjes E. S., Price J. L. (2015). Drosophila DBT autophosphorylation of its C-terminal domain antagonized by SPAG and involved in UV-induced apoptosis. Mol. Cell. Biol. 35, 2414–2424. 10.1128/MCB.00390-15 PubMed DOI PMC

Fang Y., Sathyanarayanan S., Sehgal A. (2007). Post-translational regulation of the Drosophila circadian clock requires protein phosphatase 1 (PP1). Genes Dev. 21, 1506–1518. 10.1101/gad.1541607 PubMed DOI PMC

Fustin J. M., Kojima R., Itoh K., Chang H. Y., Shiqi Y., Zhuang B., et al. (2018). Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock. Proc. Natl. Acad. Sci. U. S. A. 115, 5980–5985. 10.1073/pnas.1721371115 PubMed DOI PMC

Garbe D. S., Fang Y., Zheng X. Z., Sowcik M., Anjum R., Gygi S. P., et al. (2013). Cooperative interaction between phosphorylation sites on PERIOD maintains circadian period in Drosophila. PLoS Genet. 9, e1003749. 10.1371/journal.pgen.1003749 PubMed DOI PMC

Garcia-Concejo A., Larhammar D. (2021). Protein kinase C family evolution in jawed vertebrates. Dev. Biol. 479, 77–90. 10.1016/j.ydbio.2021.07.013 PubMed DOI

Giesecke A., Johnstone P. S., Lamaze A., Landskron J., Atay E., Chen K.-F., et al. (2021). Nuclear export of Drosophila PERIOD contributes to temperature compensation of the circadian clock. Cold Spring Harbor, NY. bioRxiv. 10.1101/2021.10.25.465663 PubMed DOI

Graves P. R., Roach P. J. (1995). Role of COOH-terminal phosphorylation in the regulation of casein kinase I delta. J. Biol. Chem. 270, 21689–21694. 10.1074/jbc.270.37.21689 PubMed DOI

Hara T., Koh K., Combs D. J., Sehgal A. (2011). Post-translational regulation and nuclear entry of TIMELESS and PERIOD are affected in new timeless mutant. J. Neurosci. 31, 9982–9990. 10.1523/JNEUROSCI.0993-11.2011 PubMed DOI PMC

Hardin P. E., Hall J. C., Rosbash M. (1990). Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343, 536–540. 10.1038/343536a0 PubMed DOI

Hogenesch J. B., Gu Y. Z., Jain S., Bradfield C. A. (1998). The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl. Acad. Sci. U. S. A. 95, 5474–5479. 10.1073/pnas.95.10.5474 PubMed DOI PMC

Hunter-Ensor M., Ousley A., Sehgal A. (1996). Regulation of the Drosophila protein timeless suggests a mechanism for resetting the circadian clock by light. Cell 84 (5), 677–685. 10.1016/s0092-8674(00)81046-6 PubMed DOI

Isojima Y., Nakajima M., Ukai H., Fujishima H., Yamada R. G., Masumoto K. H., et al. (2009). CKI epsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. Proc. Natl. Acad. Sci. U. S. A. 106, 15744–15749. 10.1073/pnas.0908733106 PubMed DOI PMC

Jang A. R., Moravcevic K., Saez L., Young M. W., Sehgal A. (2015). Drosophila TIM binds importin α1, and acts as an adapter to transport PER to the nucleus. PLoS Genet. 11, e1004974. 10.1371/journal.pgen.1004974 PubMed DOI PMC

Johnson K. P., Dietrich C. H., Friedrich F., Beutel R. G., Wipfler B., Peters R. S., et al. (2018). Phylogenomics and the evolution of hemipteroid insects. Proc. Natl. Acad. Sci. U. S. A. 115, 12775–12780. 10.1073/pnas.1815820115 PubMed DOI PMC

Joshi R., Cai Y. D., Xia Y., Chiu J. C., Emery P. (2022). PERIOD phosphoclusters control temperature compensation of the Drosophila circadian clock. Front. Physiol. 981, 888262. 10.3389/fphys.2022.888262 PubMed DOI PMC

Jursnich V. A., Fraser S. E., Held L. I., Jr., Ryerse J., Bryant P. J. (1990). Defective gap-junctional communication associated with imaginal disc overgrowth and degeneration caused by mutations of the dco gene in Drosophila. Dev. Biol. 140, 413–429. 10.1016/0012-1606(90)90090-6 PubMed DOI

Kaasik K., Kivimae S., Allen J. J., Chalkley R. J., Huang Y., Baer K., et al. (2013). Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab. 17, 291–302. 10.1016/j.cmet.2012.12.017 PubMed DOI PMC

Kawahara A. Y., Plotkin D., Espeland M., Meusemann K., Toussaint E. F. A., Donath A., et al. (2019). Phylogenomics reveals the evolutionary timing and pattern of butterflies and moths. Proc. Natl. Acad. Sci. U. S. A. 116, 22657–22663. 10.1073/pnas.1907847116 PubMed DOI PMC

King D. P., Zhao Y. L., Sangoram A. M., Wilsbacher L. D., Tanaka M., Antoch M. P., et al. (1997). Positional cloning of the mouse circadian Clock gene. Cell 89, 641–653. 10.1016/S0092-8674(00)80245-7 PubMed DOI PMC

Kivimaë S., Saez L., Young M. W. (2008). Activating PER repressor through a DBT-directed phosphorylation switch. PLoS Biol. 6, e183–e1583. 10.1371/journal.pbio.0060183 PubMed DOI PMC

Kloss B., Price J. L., Saez L., Blau J., Rothenfluh A., Wesley C. S., et al. (1998). The Drosophila clock gene double-time encodes a protein closely related to human casein kinase I epsilon. Cell 94, 97–107. 10.1016/S0092-8674(00)81225-8 PubMed DOI

Kloss B., Rothenfluh A., Young M. W., Saez L. (2001). Phosphorylation of PERIOD is influenced by cycling physical associations of DOUBLE-TIME, PERIOD, and TIMELESS in the Drosophila clock. Neuron 30, 699–706. 10.1016/S0896-6273(01)00320-8 PubMed DOI

Ko H. W., Kim E. Y., Chiu J., Vanselow J. T., Kramer A., Edery I. (2010). A hierarchical phosphorylation cascade that regulates the timing of PERIOD nuclear entry reveals novel roles for proline-directed kinases and GSK-3 beta/SGG in circadian clocks. J. Neurosci. 30, 12664–12675. 10.1523/Jneurosci.1586-10.2010 PubMed DOI PMC

Kobelkova A., Bajgar A., Dolezel D. (2010). Functional molecular analysis of a circadian clock Gene timeless promoter from the drosophilid fly Chymomyza costata. J. Biol. Rhythms 25, 399–409. 10.1177/0748730410385283 PubMed DOI

Kondo S., Ueda R. (2013). Highly improved gene targeting by germline-specific Cas9 expression in Drosophila. Genetics 195, 715–721. 10.1534/genetics.113.156737 PubMed DOI PMC

Kotwica-Rolinska J., Damulewicz M., Chodáková L., Krištofová L., Dolezel D. (2022b). Pigment Dispersing Factor is a circadian clock output and regulates photoperiodic response in the linden bug, Pyrrhocoris apterus . Front. Physiol. 13, 884909. 10.3389/fphys.2022.884909 PubMed DOI PMC

Kotwica-Rolinska J., Chodakova L., Chvalova D., Kristofova L., Fenclova I., Provaznik J., et al. (2019) CRISPR/Cas9 genome editing introduction and optimization in the non-model insect Pyrrhocoris apterus . Front. Physiology. 10: 891. 10.3389/fphys.2019.00891 PubMed DOI PMC

Kotwica-Rolinska J., Chodakova L., Smykal V., Damulewicz M., Provaznik J., Wu B. C. H., et al. (2022a). Loss of timeless Underlies an evolutionary transition within the circadian clock. Mol. Biol. Evol. 39, msab346. 10.1093/molbev/msab346 PubMed DOI PMC

Kume K., Zylka M. J., Sriram S., Shearman L. P., Weaver D. R., Jin X. W., et al. (1999). mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205. 10.1016/S0092-8674(00)81014-4 PubMed DOI

Lam V. H., Li Y. H., Liu X., Murphy K. A., Diehl J. S., Kwok R. S., et al. (2018). CK1α collaborates with DOUBLETIME to regulate PERIOD function in the Drosophila circadian clock. J. Neurosci. 38, 10631–10643. 10.1523/JNEUROSCI.0871-18.2018 PubMed DOI PMC

Lee C., Etchegaray J. P., Cagampang F. R. A., Loudon A. S. I., Reppert S. M. (2001). Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107, 855–867. 10.1016/S0092-8674(01)00610-9 PubMed DOI

Leloup J. C. (2009). Circadian clocks and phosphorylation: Insights from computational modeling. Open Life Sci. 4, 290–303. 10.2478/s11535-009-0025-1 DOI

Levine J. D., Funes P., Dowse H. B., Hall J. C. (2002). Signal analysis of behavioral and molecular cycles. BMC Neurosci. 3, 1. 10.1186/1471-2202-3-1 PubMed DOI PMC

Li Y. H., Liu X., Vanselow J. T., Zheng H., Schlosser A., Chiu J. C. (2019). O-GlcNAcylation of PERIOD regulates its interaction with CLOCK and timing of circadian transcriptional repression. PLoS Genet. 15 (1), e1007953. 10.1371/journal.pgen.1007953 PubMed DOI PMC

Lowrey P. L., Shimomura K., Antoch M. P., Yamazaki S., Zemenides P. D., Ralph M. R., et al. (2000). Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492. 10.1126/science.288.5465.483 PubMed DOI PMC

Masuda S., Narasimamurthy R., Yoshitane H., Kim J. K., Fukada Y., Virshup D. M. (2020). Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch. Proc. Natl. Acad. Sci. U. S. A. 117, 10888–10896. 10.1073/pnas.2000266117 PubMed DOI PMC

Matsumoto A., Tomioka K., Chiba Y., Tanimura T. (1999). Timrit lengthens circadian period in a temperature-dependent manner through suppression of PERIOD protein cycling and nuclear localization. Mol. Cell. Biol. 19, 4343–4354. 10.1128/mcb.19.6.4343 PubMed DOI PMC

McKenna D. D., Shin S., Ahrens D., Balke M., Beza-Beza C., Clarke D. J., et al. (2019). The evolution and genomic basis of beetle diversity. Proc. Natl. Acad. Sci. U. S. A. 116, 24729–24737. 10.1073/pnas.1909655116 PubMed DOI PMC

Meireles-Filho A. C., Amoretty P. R., Souza N. A., Kyriacou C. P., Peixoto A. A. (2006). Rhythmic expression of the cycle gene in a hematophagous insect vector. BMC Mol. Biol. 7, 38. 10.1186/1471-2199-7-38 PubMed DOI PMC

Meng Q. J., Logunova L., Maywood E. S., Gallego M., Lebiecki J., Brown T. M., et al. (2008). Setting clock speed in mammals: The CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58, 78–88. 10.1016/j.neuron.2008.01.019 PubMed DOI PMC

Meyer P., Saez L., Young M. W. (2006). PER-TIM interactions in living Drosophila cells: An interval timer for the circadian clock. Science 311, 226–229. 10.1126/science.1118126 PubMed DOI

Misof B., Liu S., Meusemann K., Peters R. S., Donath A., Mayer C., et al. (2014). Phylogenomics resolves the timing and pattern of insect evolution. Science 346, 763–767. 10.1126/science.1257570 PubMed DOI

Muskus M. J., Preuss F., Fan J. Y., Bjes E. S., Price J. L. (2007). Drosophila DBT lacking protein kinase activity produces long-period and arrhythmic circadian behavioral and molecular rhythms. Mol. Cell. Biol. 27, 8049–8064. 10.1128/Mcb.00680-07 PubMed DOI PMC

Myers M. P., Wager Smith K., Rothenfluh Hilfiker A., Young M. W., Rothenfluh-Hilfiker A. (1996). Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock. Science 271, 1736–1740. 10.1126/science.271.5256.1736 PubMed DOI

Narasimamurthy R., Hunt S. R., Lu Y., Fustin J. M., Okamura H., Partch C. L., et al. (2018). CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch. Proc. Natl. Acad. Sci. U. S. A. 115, 5986–5991. 10.1073/pnas.1721076115 PubMed DOI PMC

Narasimamurthy R., Virshup D. M. (2021). The phosphorylation switch that regulates ticking of the circadian clock. Mol. Cell 81, 1133–1146. 10.1016/j.molcel.2021.01.006 PubMed DOI

Peschel N., Chen K. F., Szabo G., Stanewsky R. (2009). Light-dependent interactions between the Drosophila circadian clock factors cryptochrome, Jetlag, and timeless. Curr. Biol. 19 (3), 241–247. 10.1016/j.cub.2008.12.042 PubMed DOI

Pfeiffenberger C., Lear B. C., Keegan K. P., Allada R. (2010). Locomotor activity level monitoring using the Drosophila Activity Monitoring (DAM) System. Cold Spring Harb. Protoc. 2010 (11), prot5518. 10.1101/pdb.prot5518 PubMed DOI

Philpott J. M., Narasimamurthy R., Ricci C. G., Freeberg A. M., Hunt S. R., Yee L. E., et al. (2020). Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch. Elife 9, e52343. 10.7554/eLife.52343 PubMed DOI PMC

Port F., Chen H. M., Lee T., Bullock S. L. (2014). Optimized CRISPR/Cas tools for efficient germline and somatic genome engineering in Drosophila. Proc. Natl. Acad. Sci. U. S. A. 111, E2967–E2976. 10.1073/pnas.1405500111 PubMed DOI PMC

Poupardin R., Schottner K., Korbelova J., Provaznik J., Dolezel D., Pavlinic D., et al. (2015). Early transcriptional events linked to induction of diapause revealed by RNAseq in larvae of drosophilid fly, Chymomyza costata. BMC Genomics 16, 720. 10.1186/s12864-015-1907-4 PubMed DOI PMC

Price J. L., Blau J., Rothenfluh A., Abodeely M., Kloss B., Young M. W. (1998). Double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95. 10.1016/S0092-8674(00)81224-6 PubMed DOI

Putker M., Wong D. C., Seinkmane E., Rzechorzek N. M., Zeng A., Hoyle N. P., et al. (2021). CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping. EMBO J. 40 (7), e106745. 10.15252/embj.2020106745 PubMed DOI PMC

Ralph M. R., Menaker M. A. (1988). A mutation of the circadian system in golden hamsters. Science 2241 (4870), 1225–1227. 10.1126/science.3413487 PubMed DOI

Reischl S., Kramer A. (2011). Kinases and phosphatases in the mammalian circadian clock. FEBS Lett. 10, 1393–1399. 10.1016/j.febslet.2011.02.038 PubMed DOI

Rothenfluh A., Abodeely M., Price J. L., Young M. W. (2000). Isolation and analysis of six timeless alleles that cause short- or long-period circadian rhythms in Drosophila. Genetics 156, 665–675. 10.1093/genetics/156.2.665 PubMed DOI PMC

Rutila J. E., Suri V., Le M., So W. V., Rosbash M., Hall J. C. (1998). CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, 805–814. 10.1016/S0092-8674(00)81441-5 PubMed DOI

Saez L., Derasmo M., Meyer P., Stieglitz J., Young M. W. (2011). A key temporal delay in the circadian cycle of Drosophila is mediated by a nuclear localization signal in the timeless protein. Genetics 188, 591–600. 10.1534/genetics.111.127225 PubMed DOI PMC

Saez L., Young M. W. (1996). Regulation of nuclear entry of the Drosophila clock proteins period and timeless. Neuron 17, 911–920. 10.1016/S08966273(00)80222-6 PubMed DOI

Sathyanarayanan S., Zheng X., Xiao R., Sehgal A. (2004). Posttranslational regulation of Drosophila PERIOD protein by protein phosphatase 2A. Cell 116, 603–615. 10.1016/s0092-8674(04)00128-x PubMed DOI

Schmid B., Helfrich-Forster C., Yoshii T. (2011). A new ImageJ plug-in “ActogramJ” for chronobiological analyses. J. Biol. Rhythms 26, 464–467. 10.1177/0748730411414264 PubMed DOI

Sehgal A., Price J. L., Man B., Young M. W. (1994). Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263, 1603–1606. 10.1126/science.8128246 PubMed DOI

Sekine T., Yamaguchi T., Hamano K., Young M. W., Shimoda M., Saez L. (2008). Casein kinase I epsilon does not rescue double-time function in Drosophila despite evolutionarily conserved roles in the circadian clock. J. Biol. Rhythms 23, 3–15. 10.1177/0748730407311652 PubMed DOI

Shinohara Y., Koyama Y. M., Ukai-Tadenuma M., Hirokawa T., Kikuchi M., Yamada R. G., et al. (2017). Temperature-sensitive substrate and product binding underlie temperature-compensated phosphorylation in the clock. Mol. Cell 67, 783–798. 10.1016/j.molcel.2017.08.009 PubMed DOI

Singh S., Giesecke A., Damulewicz M., Fexova S., Mazzotta G. M., Stanewsky R., et al. (2019). New Drosophila circadian clock mutants affecting temperature compensation induced by targeted mutagenesis of timeless . Front. Physiol. 10, 1442. 10.3389/fphys.2019.01442 PubMed DOI PMC

Smykal V., Pivarci M., Provaznik J., Bazalova O., Jedlicka P., Luksan O., et al. (2020). Complex evolution of insect insulin receptors and homologous decoy receptors, and functional significance of their multiplicity. Mol. Biol. Evol. 37, 1775–1789. 10.1093/molbev/msaa048 PubMed DOI PMC

Stanewsky R., Kaneko M., Emery P., Beretta B., Wager-Smith K., Kay S. A., et al. (1998). The cry(b) mutation identifies cryptochrome as a circadian photoreceptor in Drosophila . Cell 95, 681–692. 10.1016/S0092-8674(00)81638-4 PubMed DOI

Toh K. L., Jones C. R., He Y., Eide E. J., Hinz W. A., Virshup D. M., et al. (2001). An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043. 10.1126/science.1057499 PubMed DOI

Top D., O'Neil J. L., Merz G. E., Dusad K., Crane B. R., Young M. W. (2018). CK1/Doubletime activity delays transcription activation in the circadian clock. Elife 7, e32679. 10.7554/eLife.32679 PubMed DOI PMC

Tosini G., Menaker M. (1998). The tau mutation affects temperature compensation of hamster retinal circadian oscillators. Neuroreport 9, 1001–1005. 10.1097/00001756-199804200-00009 PubMed DOI

Uno Y., Nishida C., Takagi C., Ueno N., Matsuda Y. (2013). Homoeologous chromosomes of Xenopus laevis are highly conserved after whole-genome duplication. Hered. (Edinb) 111 (5), 430–436. 10.1038/hdy.2013.65 PubMed DOI PMC

Venkatesan A., Fan J. Y., Bouyain S., Price J. L. (2019). The circadian tau mutation in casein kinase 1 is part of a larger domain that can Be mutated to shorten circadian period. Int. J. Mol. Sci. 20, 813. 10.3390/ijms20040813 PubMed DOI PMC

Venkatesan A., Fan J. Y., Nauman C., Price J. L. (2015). A doubletime nuclear localization signal mediates an interaction with bride of doubletime to promote circadian function. J. Biol. Rhythms 30, 302–317. 10.1177/0748730415588189 PubMed DOI PMC

Vielhaber E. L., Duricka D., Ullman K. S., Virshup D. M. (2001). Nuclear export of mammalian PERIOD proteins. J. Biol. Chem. 276 (49), 45921–45927. 10.1074/jbc.M107726200 PubMed DOI PMC

Wipfler B., Letsch H., Frandsen P. B., Kapli P., Mayer C., Bartel D., et al. (2019). Evolutionary history of Polyneoptera and its implications for our understanding of early winged insects. Proc. Natl. Acad. Sci. U. S. A. 116 (8), 3024–3029. 10.1073/pnas.1817794116 PubMed DOI PMC

Wulbeck C., Szabo G., Shafer O. T., Helfrich-Forster C., Stanewsky R. (2005). The novel Drosophila tim(blind) mutation affects behavioral rhythms but not periodic eclosion. Genetics 169 (2), 751–766. 10.1534/genetics.104.036244 PubMed DOI PMC

Xu Y., Padiath Q. S., Shapiro R. E., Jones C. R., Wu S. C., Saigoh N., et al. (2005). Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434, 640–644. 10.1038/nature03453 PubMed DOI

Xu Y., Toh K. L., Jones C. R., Shin J. Y., Fu Y. H., Ptacek L. J. (2007). Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 128, 59–70. 10.1016/j.cell.2006.11.043 PubMed DOI PMC

Yildiz O., Doi M., Yujnovsky I., Cardone L., Berndt A., Hennig S., et al. (2005). Crystal structure and interactions of the PAS repeat region of the Drosophila clock protein PERIOD. Mol. Cell 17 (1), 69–82. 10.1016/j.molcel.2004.11.022 PubMed DOI

Yu W. J., Zheng H., Price J. L., Hardin P. E. (2009). DOUBLETIME plays a noncatalytic role to mediate CLOCK phosphorylation and repress CLOCK-dependent transcription within the Drosophila circadian clock. Mol. Cell. Biol. 29 (6), 1452–1458. 10.1128/Mcb.01777-08 PubMed DOI PMC

Zeng H. K., Qian Z. W., Myers M. P., Rosbash M. (1996). A light-entrainment mechanism for the Drosophila circadian clock. Nature 380 (6570), 129–135. 10.1038/380129a0 PubMed DOI

Zhou M., Kim J. K., Eng G. W., Forger D. B., Virshup D. M. (2015). A Period2 phosphoswitch regulates and temperature compensates circadian period. Mol. Cell 60, 77–88. 10.1016/j.molcel.2015.08.022 PubMed DOI

Zilian O., Frei E., Burke R., Brentrup D., Gutjahr T., Bryant P. J., et al. (1999). double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs. Development 126 (23), 5409–5420. 10.1242/dev.126.23.5409 PubMed DOI

Zylka M. J., Shearman L. P., Weaver D. R., Reppert S. M. (1998). Three period homologs in mammals: Differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20, 1103–1110. 10.1016/S0896-6273(00)80492-4 PubMed DOI

Impact of photoperiod and functional clock on male diapause in cryptochrome and pdf mutants in the linden bug Pyrrhocoris apterus

Steroid receptor coactivator TAIMAN is a new modulator of insect circadian clock