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Title: TIMELESS mutation alters phase responsiveness and causes advanced sleep phase

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 (h TIM) 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). Here, we conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1]; ORCiD logo [3];  [4];  [4];  [5];  [1];  [1]
  1. Univ. of California, San Francisco, CA (United States)
  2. Univ. of California, San Francisco, CA (United States); System1 Biosciences, San Francisco, CA (United States)
  3. Soochow Univ., Suzhou (China)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
  5. Univ. of Utah, Salt Lake City, UT (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1596675
Grant/Contract Number:  
[AC02-05CH11231; NS072360; HL059596; P30 DK063720]
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
[ Journal Volume: 116; Journal Issue: 24]; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; TIMELESS; human genetics; mammalian circadian clock regulation; familial advanced sleep phase

Citation Formats

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, and Ptáček, Louis J. TIMELESS mutation alters phase responsiveness and causes advanced sleep phase. United States: N. p., 2019. Web. doi:10.1073/pnas.1819110116.
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. TIMELESS mutation alters phase responsiveness and causes advanced sleep phase. United States. doi:10.1073/pnas.1819110116.
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, and Ptáček, Louis J. Tue . "TIMELESS mutation alters phase responsiveness and causes advanced sleep phase". United States. doi:10.1073/pnas.1819110116.
@article{osti_1596675,
title = {TIMELESS mutation alters phase responsiveness and causes advanced sleep phase},
author = {Kurien, Philip and Hsu, Pei-Ken and Leon, Jacy and Wu, David and McMahon, Thomas and Shi, Guangsen and Xu, Ying and Lipzen, Anna and Pennacchio, Len A. and Jones, Christopher R. and Fu, Ying-Hui and Ptáček, Louis J.},
abstractNote = {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). Here, 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 = {10.1073/pnas.1819110116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = [24],
volume = [116],
place = {United States},
year = {2019},
month = {5}
}

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