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

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.