Abstract
The mammalian circadian clock regulates the daily cycles of many important physiological processes, but its mechanism is not well understood. Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. Knockout of MTA1 in mice disrupts the free-running period of circadian rhythms under constant light and normal entrainment of behaviour to 12-h-light/12-h-dark cycles. The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. Moreover, MTA1 deacetylates BMAL1 at lysine 538 through regulating deacetylase SIRT1 expression, thus disturbing the CRY1-mediated negative feedback loop. These findings uncover a previously unappreciated role for MTA1 in maintenance of circadian rhythmicity through acting on the positive limb of the clock machinery.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ARNTL Transcription Factors / genetics
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ARNTL Transcription Factors / metabolism
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Acetylation
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Animals
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Behavior, Animal
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CLOCK Proteins / genetics
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CLOCK Proteins / metabolism
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Circadian Rhythm / genetics*
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Cryptochromes / genetics
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Cryptochromes / metabolism
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Feedback, Physiological
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Female
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Gene Expression Regulation*
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Histone Deacetylases / genetics*
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Histone Deacetylases / metabolism
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Humans
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Male
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Mice
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Mice, Knockout
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Motor Activity / genetics
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Photoperiod
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Promoter Regions, Genetic
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Protein Multimerization
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism
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Signal Transduction
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Sirtuin 1 / genetics
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Sirtuin 1 / metabolism
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Trans-Activators
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Transcription Factors / deficiency
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Transcription Factors / genetics*
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Transcription, Genetic*
Substances
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ARNTL Transcription Factors
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Bmal1 protein, mouse
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Cry1 protein, mouse
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Cryptochromes
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MTA1 protein, human
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Mta1 protein, mouse
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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CLOCK Proteins
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Clock protein, mouse
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Sirt1 protein, mouse
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Sirtuin 1
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Histone Deacetylases