Circadian Clock Control by SUMOylation of BMAL1

Cardone, Luca; Hirayama, Jun; Giordano, Francesca; Tamaru, Teruya; Palvimo, Jorma J.; Sassone–Corsi, Paolo

doi:10.1126/science.1110689

Cited by 284 publications

(224 citation statements)

References 29 publications

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“…A recent study revealed that constitutive high expression of BMAL1 protein in Rev-Erb␣-disrupted mice still allows robust circadian molecular and behavioral rhythms (12). Moreover, it has been shown that sumoylation of BMAL1 influences posttranscriptional features of BMAL1 and that this process is CLOCK-dependent (13). Taken together, these results suggest that posttranslational modification of BMAL1 is an important prerequisite for its performance in the circadian oscillator.…”

supporting

confidence: 56%

The BMAL1 C terminus regulates the circadian transcription feedback loop

Kiyohara

Tagao

Tamanini

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

103

135

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The circadian clock is driven by cell-autonomous transcription͞ translation feedback loops. The BMAL1 transcription factor is an indispensable component of the positive arm of this molecular oscillator in mammals. Here, we present a molecular genetic screening assay for mutant circadian clock proteins that is based on real-time circadian rhythm monitoring in cultured fibroblasts. By using this assay, we identified a domain in the extreme C terminus of BMAL1 that plays an essential role in the rhythmic control of E-box-mediated circadian transcription. Remarkably, the last 43 aa of BMAL1 are required for transcriptional activation, as well as for association with the circadian transcriptional repressor CRYPTO-CHROME 1 (CRY1), depending on the coexistence of CLOCK protein. C-terminally truncated BMAL1 mutant proteins still associate with mPER2 (another protein of the negative feedback loop), suggesting that an additional repression mechanism may converge on the N terminus. Taken together, these results suggest that the C-terminal region of BMAL1 is involved in determining the balance between circadian transcriptional activation and suppression.circadian clock ͉ real-time monitor T he mammalian circadian clock is a highly dynamic system that generates periodic fluctuations in the mRNA expression levels of hundreds of genes to confer near 24-h rhythmicity to behavior, physiology, and metabolic processes, thereby allowing mammals to anticipate the momentum of the day (1). The master clock resides in the suprachiasmatic nuclei (SCN) of the brain and, in turn, synchronizes circadian clocks in peripheral tissues (2). Even fibroblasts in culture contain an active circadian clock that has the same genetic makeup of the central clock in the SCN (3-6). To keep pace with the day-night cycle, the SCN clock, but not peripheral clocks, are entrained by light.Circadian rhythms are generated by a molecular oscillator that consists of intertwined positive and negative transcription͞ translation feedback loops involving a set of clock genes (7) and clock-controlled output genes that link the oscillator to clockcontrolled processes (8). BMAL1 (MOP3) and CLOCK are basic helix-loop-helix PAS transcription factors that heterodimerize and (by means of binding to E-box promoter elements) transactivate the Period (Per1 and Per2) and Cryptochrome (Cry1 and Cry2) genes and an orphan nuclear receptor Rev-Erb␣ core oscillator gene. Subsequently, PER and CRY proteins act as negative elements by inhibiting the activity of the CLOCK͞BMAL1 heterodimer, whereas REV-ERB␣ negatively regulates Bmal1 gene expression (1, 9). The above feedback mechanism is supported by biochemical, molecular, and genetic evidence; however, formal proof of its requirement in the maintenance of circadian clock oscillations has not been shown thus far.Genetic ablation of mBmal1 results in complete disruption of the mammalian circadian clock at the behavioral and molecular levels (10). However, except for the PAS elements, which are required for association with CLOCK (11)...

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supporting

confidence: 56%

The BMAL1 C terminus regulates the circadian transcription feedback loop

Kiyohara

Tagao

Tamanini

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

103

135

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“…CLOCK, BMAL1, PER, and possibly also CRY proteins are phosphoproteins in vivo (Lee et al 2001). Moreover, BMAL1 was shown to be sumoylated (Cardone et al 2005) and, very recently, acetylated (Grimaldi et al, this volume). These modifications specifically alter the properties and functionality of the corresponding proteins by changing protein stability, subcellular localization, activity, or complex formation.…”

Section: Introductionmentioning

confidence: 99%

Role of Phosphorylation in the Mammalian Circadian Clock

Vanselow¹,

Kramer²

2007

Cold Spring Harbor Symposia on Quantitative Biology

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Circadian clocks regulate a wide variety of processes ranging from gene expression to behavior. At the molecular level, circadian rhythms are thought to be produced by a set of clock genes and proteins interconnected to form transcriptional-translational feedback loops. Rhythmic gene expression was formerly regarded as the major drive for rhythms in clock protein abundance, but recent findings underline the crucial importance of posttranslational mechanisms for both the generation and dynamics of circadian rhythms. In particular, the reversible phosphorylation of PER proteins-essential components within the negative feedback loop in Drosophila and mammals-seems to have a key role for the correct timing of nuclear repression. To understand how PER protein phosphorylation regulates the dynamics of the circadian oscillator, we have mapped endogenous phosphorylation sites in mPER2. Detailed investigation of the functional role of one particular phosphorylation site (Ser-659, which is mutated in the familial advanced sleep phase syndrome [FASPS]) led us propose a model of functionally different phosphorylation sites in PER2. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster.

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“…Other posttranslational modifications have also been found on core clock proteins. Thus, CLOCK can be sumoylated (Cardone et al 2005) (Asher et al 2010). PER2 and BMAL1 can be acetylated (by CLOCK [Doi et al 2006;Grimaldi et al 2009] and, probably, additional acetyltransferases) and deacetylated in a circadian fashion by the NAD þ -dependent deacetylase Sirtuin 1 (SIRT1) (Asher et al 2008;Nakahata et al 2008).…”

mentioning

confidence: 99%

The Mammalian Circadian Timing System: Synchronization of Peripheral Clocks

Saini

Suter²,

Liani³

et al. 2011

Cold Spring Harbor Symposia on Quantitative Biology

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Mammalian physiology has to adapt to daily alternating periods during which animals either forage and feed or sleep and fast. The adaptation of physiology to these oscillations is controlled by a circadian timekeeping system, in which a master pacemaker in the suprachiasmatic nucleus (SCN) synchronizes slave clocks in peripheral organs. Because the temporal coordination of metabolism is a major purpose of clocks in many tissues, it is important that metabolic and circadian cycles are tightly coordinated. Recent studies have revealed a multitude of signaling components that possibly link metabolism to circadian gene expression. Owing to this redundancy, the implication of any single signaling pathway in the synchronization of peripheral oscillators cannot be assessed by determining the steady-state phase, but instead requires the monitoring of phase-shifting kinetics at a high temporal resolution.

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Circadian Clock Control by SUMOylation of BMAL1

Cited by 284 publications

References 29 publications

The BMAL1 C terminus regulates the circadian transcription feedback loop

The BMAL1 C terminus regulates the circadian transcription feedback loop

Role of Phosphorylation in the Mammalian Circadian Clock

The Mammalian Circadian Timing System: Synchronization of Peripheral Clocks

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