Metastasis-associated protein 1 is an integral component of the circadian molecular machinery

Da-Qiang Li, Suresh B. Pakala, Sirigiri Divijendra Natha Reddy, Shaohua Peng, Seetharaman Balasenthil, Chu-Xia Deng, Cheng Chi Lee, Michael A. Rea and Rakesh Kumar ()
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Da-Qiang Li: School of Medicine and Health Sciences, The George Washington University
Suresh B. Pakala: School of Medicine and Health Sciences, The George Washington University
Sirigiri Divijendra Natha Reddy: School of Medicine and Health Sciences, The George Washington University
Shaohua Peng: University of Texas M. D. Anderson Cancer Center
Seetharaman Balasenthil: University of Texas M. D. Anderson Cancer Center
Chu-Xia Deng: Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Cheng Chi Lee: University of Texas Health Science Center-Houston
Michael A. Rea: Circadian Neurobiology Laboratory, The University of Houston
Rakesh Kumar: School of Medicine and Health Sciences, The George Washington University

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3545

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