Abstract
The Timeless protein is essential for circadian rhythm in Drosophila. The Timeless orthologue in mice is essential for viability and appears to be required for the maintenance of a robust circadian rhythm as well. We have found that the human Timeless protein interacts with both the circadian clock protein cryptochrome 2 and with the cell cycle checkpoint proteins Chk1 and the ATR-ATRIP complex and plays an important role in the DNA damage checkpoint response. Down-regulation of Timeless in human cells seriously compromises replication and intra-S checkpoints, indicating an intimate connection between the circadian cycle and the DNA damage checkpoints that is in part mediated by the Timeless protein.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle / physiology*
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Cell Cycle Proteins / metabolism
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Cell Line
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Checkpoint Kinase 1
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Chromatin Assembly and Disassembly / physiology
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Circadian Rhythm / physiology*
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Cryptochromes
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DNA Damage*
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DNA Replication / drug effects
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DNA Replication / physiology
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DNA-Binding Proteins
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Down-Regulation / drug effects
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Exodeoxyribonucleases / metabolism
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Flavoproteins / metabolism
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Humans
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Hydroxyurea / pharmacology
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins / metabolism
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
Substances
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ATRIP protein, human
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Cryptochromes
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DNA-Binding Proteins
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Flavoproteins
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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RNA, Small Interfering
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TIMELESS protein, human
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Timeless protein, mouse
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Transcription Factors
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Protein Kinases
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Protein Serine-Threonine Kinases
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Exodeoxyribonucleases
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three prime repair exonuclease 1
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Hydroxyurea