TIMELESS mutation alters phase responsiveness and causes advanced sleep phase
Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with alt...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2019-06, Vol.116 (24), p.12045-12053 |
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| creator | Kurien, Philip Hsu, Pei-Ken Leon, Jacy Wu, David McMahon, Thomas Shi, Guangsen Xu, Ying Lipzen, Anna Pennacchio, Len A. Jones, Christopher R. Fu, Ying-Hui Ptáček, Louis J. |
| description | Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP. |
| doi_str_mv | 10.1073/pnas.1819110116 |
| format | Article |
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Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1819110116</identifier><identifier>PMID: 31138685</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; BASIC BIOLOGICAL SCIENCES ; Biological Sciences ; Cell Cycle Proteins - genetics ; Cell Line ; Circadian Clocks - genetics ; Circadian rhythm ; Circadian Rhythm - genetics ; Circadian rhythms ; CRISPR ; Cryptochromes ; Destabilization ; Embryo fibroblasts ; Embryos ; Entrainment ; familial advanced sleep phase ; Fibroblasts ; Fibroblasts - physiology ; HEK293 Cells ; human genetics ; Humans ; Intracellular Signaling Peptides and Proteins - genetics ; Light ; Male ; mammalian circadian clock regulation ; Mammals ; Mice ; Mice, Inbred C57BL ; Mutation ; Mutation - genetics ; PNAS Plus ; Regulators ; Sleep ; Sleep - genetics ; TIMELESS ; Timeless protein</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2019-06, Vol.116 (24), p.12045-12053</ispartof><rights>Copyright National Academy of Sciences Jun 11, 2019</rights><rights>2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-f6899ff233034cd4e71dd041297bf2613aa4655e302aae6879642b38a285f8c73</citedby><cites>FETCH-LOGICAL-c470t-f6899ff233034cd4e71dd041297bf2613aa4655e302aae6879642b38a285f8c73</cites><orcidid>0000-0002-6689-7768 ; 0000000266897768</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26743517$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26743517$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31138685$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1596675$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Kurien, Philip</creatorcontrib><creatorcontrib>Hsu, Pei-Ken</creatorcontrib><creatorcontrib>Leon, Jacy</creatorcontrib><creatorcontrib>Wu, David</creatorcontrib><creatorcontrib>McMahon, Thomas</creatorcontrib><creatorcontrib>Shi, Guangsen</creatorcontrib><creatorcontrib>Xu, Ying</creatorcontrib><creatorcontrib>Lipzen, Anna</creatorcontrib><creatorcontrib>Pennacchio, Len A.</creatorcontrib><creatorcontrib>Jones, Christopher R.</creatorcontrib><creatorcontrib>Fu, Ying-Hui</creatorcontrib><creatorcontrib>Ptáček, Louis J.</creatorcontrib><creatorcontrib>Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)</creatorcontrib><title>TIMELESS mutation alters phase responsiveness and causes advanced sleep phase</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.</description><subject>Animals</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biological Sciences</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Line</subject><subject>Circadian Clocks - genetics</subject><subject>Circadian rhythm</subject><subject>Circadian Rhythm - genetics</subject><subject>Circadian rhythms</subject><subject>CRISPR</subject><subject>Cryptochromes</subject><subject>Destabilization</subject><subject>Embryo fibroblasts</subject><subject>Embryos</subject><subject>Entrainment</subject><subject>familial advanced sleep phase</subject><subject>Fibroblasts</subject><subject>Fibroblasts - physiology</subject><subject>HEK293 Cells</subject><subject>human genetics</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Light</subject><subject>Male</subject><subject>mammalian circadian clock regulation</subject><subject>Mammals</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>PNAS Plus</subject><subject>Regulators</subject><subject>Sleep</subject><subject>Sleep - genetics</subject><subject>TIMELESS</subject><subject>Timeless protein</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkctv00AQxlcIRNPCmRPIohcuaff9uFRCVYBKqTi0nFeb9Zg4cnbNjh2J_x5HLuFxmpHmN988PkLeMHrFqBHXfQp4xSxzjFHG9DOyYNSxpZaOPicLSrlZWsnlGTlH3FFKnbL0JTkTjAmrrVqQ-8e7-9V69fBQ7cchDG1OVegGKFj124BQFcA-J2wPkACxCqmuYhgRprQ-hBShrrAD6Gf8FXnRhA7h9VO8IN8-rR5vvyzXXz_f3X5cL6M0dFg22jrXNFwIKmSsJRhW11Qy7sym4ZqJEKRWCgTlIYC2xmnJN8IGblVjoxEX5GbW7cfNHuoIaSih831p96H89Dm0_t9Karf-ez54rYxi2k0C72eBjEPrMbYDxG3MKUEcPFNOa6Mm6MPTlJJ_jICD37cYoetCgjyi51wwq6Y36gm9_A_d5bGk6QcTJZVW3Imj4PVMxZIRCzSnjRn1Rz_90U__x8-p493fh5743wZOwNsZ2OGQy6nOtZFCMSN-ASE8pKs</recordid><startdate>20190611</startdate><enddate>20190611</enddate><creator>Kurien, Philip</creator><creator>Hsu, Pei-Ken</creator><creator>Leon, Jacy</creator><creator>Wu, David</creator><creator>McMahon, Thomas</creator><creator>Shi, Guangsen</creator><creator>Xu, Ying</creator><creator>Lipzen, Anna</creator><creator>Pennacchio, Len A.</creator><creator>Jones, Christopher R.</creator><creator>Fu, Ying-Hui</creator><creator>Ptáček, Louis J.</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6689-7768</orcidid><orcidid>https://orcid.org/0000000266897768</orcidid></search><sort><creationdate>20190611</creationdate><title>TIMELESS mutation alters phase responsiveness and causes advanced sleep phase</title><author>Kurien, Philip ; Hsu, Pei-Ken ; Leon, Jacy ; Wu, David ; McMahon, Thomas ; Shi, Guangsen ; Xu, Ying ; Lipzen, Anna ; Pennacchio, Len A. ; Jones, Christopher R. ; Fu, Ying-Hui ; Ptáček, Louis J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-f6899ff233034cd4e71dd041297bf2613aa4655e302aae6879642b38a285f8c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Biological Sciences</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Line</topic><topic>Circadian Clocks - genetics</topic><topic>Circadian rhythm</topic><topic>Circadian Rhythm - genetics</topic><topic>Circadian rhythms</topic><topic>CRISPR</topic><topic>Cryptochromes</topic><topic>Destabilization</topic><topic>Embryo fibroblasts</topic><topic>Embryos</topic><topic>Entrainment</topic><topic>familial advanced sleep phase</topic><topic>Fibroblasts</topic><topic>Fibroblasts - physiology</topic><topic>HEK293 Cells</topic><topic>human genetics</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - genetics</topic><topic>Light</topic><topic>Male</topic><topic>mammalian circadian clock regulation</topic><topic>Mammals</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>PNAS Plus</topic><topic>Regulators</topic><topic>Sleep</topic><topic>Sleep - genetics</topic><topic>TIMELESS</topic><topic>Timeless protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kurien, Philip</creatorcontrib><creatorcontrib>Hsu, Pei-Ken</creatorcontrib><creatorcontrib>Leon, Jacy</creatorcontrib><creatorcontrib>Wu, David</creatorcontrib><creatorcontrib>McMahon, Thomas</creatorcontrib><creatorcontrib>Shi, Guangsen</creatorcontrib><creatorcontrib>Xu, Ying</creatorcontrib><creatorcontrib>Lipzen, Anna</creatorcontrib><creatorcontrib>Pennacchio, Len A.</creatorcontrib><creatorcontrib>Jones, Christopher R.</creatorcontrib><creatorcontrib>Fu, Ying-Hui</creatorcontrib><creatorcontrib>Ptáček, Louis J.</creatorcontrib><creatorcontrib>Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kurien, Philip</au><au>Hsu, Pei-Ken</au><au>Leon, Jacy</au><au>Wu, David</au><au>McMahon, Thomas</au><au>Shi, Guangsen</au><au>Xu, Ying</au><au>Lipzen, Anna</au><au>Pennacchio, Len A.</au><au>Jones, Christopher R.</au><au>Fu, Ying-Hui</au><au>Ptáček, Louis J.</au><aucorp>Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TIMELESS mutation alters phase responsiveness and causes advanced sleep phase</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2019-06-11</date><risdate>2019</risdate><volume>116</volume><issue>24</issue><spage>12045</spage><epage>12053</epage><pages>12045-12053</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (hTIM) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). We conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>31138685</pmid><doi>10.1073/pnas.1819110116</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-6689-7768</orcidid><orcidid>https://orcid.org/0000000266897768</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals BASIC BIOLOGICAL SCIENCES Biological Sciences Cell Cycle Proteins - genetics Cell Line Circadian Clocks - genetics Circadian rhythm Circadian Rhythm - genetics Circadian rhythms CRISPR Cryptochromes Destabilization Embryo fibroblasts Embryos Entrainment familial advanced sleep phase Fibroblasts Fibroblasts - physiology HEK293 Cells human genetics Humans Intracellular Signaling Peptides and Proteins - genetics Light Male mammalian circadian clock regulation Mammals Mice Mice, Inbred C57BL Mutation Mutation - genetics PNAS Plus Regulators Sleep Sleep - genetics TIMELESS Timeless protein |
| title | TIMELESS mutation alters phase responsiveness and causes advanced sleep phase |
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