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dc.contributor.authorJoshi, Radhika
dc.contributor.authorCai, Yao D.
dc.contributor.authorXia, Yongliang
dc.contributor.authorChiu, Joanna C.
dc.contributor.authorEmery, Patrick
dc.date2022-08-11T08:08:34.000
dc.date.accessioned2022-08-23T15:59:48Z
dc.date.available2022-08-23T15:59:48Z
dc.date.issued2021-12-24
dc.date.submitted2022-06-09
dc.identifier.citation<p>bioRxiv 2021.12.23.474078; doi: https://doi.org/10.1101/2021.12.23.474078. <a href="https://doi.org/10.1101/2021.12.23.474078" target="_blank">Link to preprint on bioRxiv.</a></p>
dc.identifier.doi10.1101/2021.12.23.474078
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30749
dc.description<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.</p>
dc.description.abstractTemperature compensation is a critical feature of circadian rhythms, but how it is achieved remains elusive. Here, we uncovered the important role played by the Drosophila PERIOD (PER) phosphodegron in temperature compensation. Using CRISPR-Cas9, we introduced a series of mutations that altered three Serines (S44, 45 and 47) belonging to the PER phosphodegron, the functional homolog of mammalian PER2’s S487 phosphodegron, which impacts temperature compensation. While all three Serine to Alanine substitutions lengthened period at all temperatures tested, temperature compensation was differentially affected. S44A and S45A substitutions caused decreased temperature compensation, while S47A resulted in overcompensation. These results thus reveal unexpected functional heterogeneity of phosphodegron residues in thermal compensation. Furthermore, mutations impairing phosphorylation of the pers phosphocluster decreased thermal compensation, consistent with its inhibitory role on S47 phosphorylation. Interestingly, the S47A substitution caused increased accumulation of hyper-phosphorylated PER at warmer temperatures. This finding was corroborated by cell culture assays in which S47A resulted in excessive temperature compensation of phosphorylation-dependent PER degradation. Thus, we show a novel role of the PER phosphodegron in temperature compensation through temperature-dependent modulation of the abundance of hyper-phosphorylated PER. Our work also reveals interesting mechanistic convergences and differences between mammalian and Drosophila temperature compensation of the circadian clock.
dc.language.isoen_US
dc.relation<p>Now published in <em>Frontiers in Physiology</em> doi: <a href="http://dx.doi.org/10.3389/fphys.2022.888262" target="_blank">10.3389/fphys.2022.888262</a></p>
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectcircadian rhythms
dc.subjectphosphodegron
dc.subjecttemperature compensation
dc.subjectcircadian clock
dc.subjectDrosophila
dc.subjectCellular and Molecular Physiology
dc.subjectGenetics and Genomics
dc.subjectNeuroscience and Neurobiology
dc.titlePERIOD phosphoclusters control temperature compensation of the Drosophila circadian clock [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3250&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/2220
dc.identifier.contextkey29630425
refterms.dateFOA2022-08-23T15:59:48Z
html.description.abstract<p>Temperature compensation is a critical feature of circadian rhythms, but how it is achieved remains elusive. Here, we uncovered the important role played by the <em>Drosophila</em> PERIOD (PER) phosphodegron in temperature compensation. Using CRISPR-Cas9, we introduced a series of mutations that altered three Serines (S44, 45 and 47) belonging to the PER phosphodegron, the functional homolog of mammalian PER2’s S487 phosphodegron, which impacts temperature compensation. While all three Serine to Alanine substitutions lengthened period at all temperatures tested, temperature compensation was differentially affected. S44A and S45A substitutions caused decreased temperature compensation, while S47A resulted in overcompensation. These results thus reveal unexpected functional heterogeneity of phosphodegron residues in thermal compensation. Furthermore, mutations impairing phosphorylation of the <em>per</em><sup><em>s</em></sup> phosphocluster decreased thermal compensation, consistent with its inhibitory role on S47 phosphorylation. Interestingly, the S47A substitution caused increased accumulation of hyper-phosphorylated PER at warmer temperatures. This finding was corroborated by cell culture assays in which S47A resulted in excessive temperature compensation of phosphorylation-dependent PER degradation. Thus, we show a novel role of the PER phosphodegron in temperature compensation through temperature-dependent modulation of the abundance of hyper-phosphorylated PER. Our work also reveals interesting mechanistic convergences and differences between mammalian and <em>Drosophila</em> temperature compensation of the circadian clock.</p>
dc.identifier.submissionpathfaculty_pubs/2220
dc.contributor.departmentEmery Lab
dc.contributor.departmentDepartment of Neurobiology


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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.