Coactivation of the CLOCK–BMAL1 complex by CBP mediates resetting of the circadian clock

Lee, Yool; Lee, Jiwon; Kwon, Ilmin; Nakajima, Yoshihiro; Ohmiya, Yoshihiro; Son, Gi Hoon; Lee, Kun Ho; Kim, Kyungjin

doi:10.1242/jcs.070300

Cited by 99 publications

(93 citation statements)

References 63 publications

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“…The decreased activation levels of per and tim mRNA in the brain of the monarch mutant lacking the BMAL1 TAD α-helix are consistent with its function as an activation domain and may explain the behavioral phase delay observed in vivo, as activation levels have previously been correlated to phase or period determination (31). In mammals, transcriptional activation occurs through the recruitment of coactivators such as CBP/p300 to BMAL1 (14,32,33), and repression by CRY1 is thought to occur through competition for binding with CBP/p300 on the BMAL1 TAD α-helix and the most distal C-terminal residues (14). As expected if dpCLK:dpBMAL1 activates transcription through a conserved mechanism involving recruitment of p300, knocking down endogenous Drosophila p300 in S2 cells substantially reduced dpCLK: dpBMAL1-mediated activation (Fig.…”

Section: Discussionsupporting

confidence: 56%

Vertebrate-like CRYPTOCHROME 2 from monarch regulates circadian transcription via independent repression of CLOCK and BMAL1 activity

Zhang

Markert

Groves

et al. 2017

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

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Circadian repression of CLOCK-BMAL1 by PERIOD and CRYPTOCHROME (CRY) in mammals lies at the core of the circadian timekeeping mechanism. CRY repression of CLOCK-BMAL1 and regulation of circadian period are proposed to rely primarily on competition for binding with coactivators on an α-helix located within the transactivation domain (TAD) of the BMAL1 C terminus. This model has, however, not been tested in vivo. Here, we applied CRISPR/Cas9-mediated mutagenesis in the monarch butterfly (Danaus plexippus), which possesses a vertebrate-like CRY (dpCRY2) and an ortholog of BMAL1, to show that insect CRY2 regulates circadian repression through TAD α-helix-dependent and -independent mechanisms. Monarch mutants lacking the BMAL1 C terminus including the TAD exhibited arrhythmic eclosion behavior. In contrast, mutants lacking the TAD α-helix but retaining the most distal C-terminal residues exhibited robust rhythms during the first day of constant darkness (DD1), albeit with a delayed peak of eclosion. Phase delay in this mutant on DD1 was exacerbated in the presence of a single functional allele of dpCry2, and rhythmicity was abolished in the absence of dpCRY2. Reporter assays in Drosophila S2 cells further revealed that dpCRY2 represses through two distinct mechanisms: a TADdependent mechanism that involves the dpBMAL1 TAD α-helix and dpCLK W328 and a TAD-independent mechanism involving dpCLK E333. Together, our results provide evidence for independent mechanisms of vertebrate-like CRY circadian regulation on the BMAL1 C terminus and the CLK PAS-B domain and demonstrate the importance of a BMAL1 TAD-independent mechanism for generating circadian rhythms in vivo.circadian clock | CRYPTOCHROME 2 | BMAL1 C terminus | CLOCK | CRISPR

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Section: Discussionsupporting

confidence: 56%

Vertebrate-like CRYPTOCHROME 2 from monarch regulates circadian transcription via independent repression of CLOCK and BMAL1 activity

Zhang

Markert

Groves

et al. 2017

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

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“…Most likely, CLOCK acts in concert with other histone acetyltransferases (HATs) to sustain cycles in the acetylation state of histones at promoters of CCGs (23). Indeed, the CLOCK: BMAL1 heterodimer has been shown to interact with CREB binding protein (CBP), p300, and with the CBP-associated factor PCAF (23)(24)(25)(26). Acetylation by these various HATs is counterbalanced by a number of histone deacetylases (HDACs).…”

Section: Circadian Rhythms In the Chromatin Fibermentioning

confidence: 99%

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

Aguilar-Arnal

Sassone–Corsi

2014

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

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Circadian rhythms drive the temporal organization of a wide variety of physiological and behavioral functions in ∼24-h cycles. This control is achieved through a complex program of gene expression. In mammals, the molecular clock machinery consists of interconnected transcriptional-translational feedback loops that ultimately ensure the proper oscillation of thousands of genes in a tissue-specific manner. To achieve circadian transcriptional control, chromatin remodelers serve the clock machinery by providing appropriate oscillations to the epigenome. Recent findings have revealed the presence of circadian interactomes, nuclear "hubs" of genome topology where coordinately expressed circadian genes physically interact in a spatial and temporal-specific manner. Thus, a circadian nuclear landscape seems to exist, whose interplay with metabolic pathways and clock regulators translates into specific transcriptional programs. Deciphering the molecular mechanisms that connect the circadian clock machinery with the nuclear landscape will reveal yet unexplored pathways that link cellular metabolism to epigenetic control.circadian rhythms | chromatin | epigenetics | nuclear organization

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“…29,30 To achieve this, we constructed various plasmids encoding the N-terminal half (VN) or C-terminal half (VC) of Venus fused to the target proteins. U2OS cells co-transfected with VN-p53 and VCcatalase exhibited only a faint BiFC signal, which markedly increased after UV treatment (Figures 5a and c).…”

Section: **mentioning

confidence: 99%

The critical role of catalase in prooxidant and antioxidant function of p53

et al. 2012

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The tumor suppressor p53 is an important regulator of intracellular reactive oxygen species (ROS) levels, although downstream mediators of p53 remain to be elucidated. Here, we show that p53 and its downstream targets, p53-inducible ribonucleotide reductase (p53R2) and p53-inducible gene 3 (PIG3), physically and functionally interact with catalase for efficient regulation of intracellular ROS, depending on stress intensity. Under physiological conditions, the antioxidant functions of p53 are mediated by p53R2, which maintains increased catalase activity and thereby protects against endogenous ROS. After genotoxic stress, high levels of p53 and PIG3 cooperate to inhibit catalase activity, leading to a shift in the oxidant/antioxidant balance toward an oxidative status, which could augment apoptotic cell death. These results highlight the essential role of catalase in p53-mediated ROS regulation and suggest that the p53/p53R2-catalase and p53/PIG3-catalase pathways are critically involved in intracellular ROS regulation under physiological conditions and during the response to DNA damage, respectively. Reactive oxygen species (ROS) are generated as products or by-products in cells and function as signaling molecules and cellular toxicants.1,2 Therefore, a series of antioxidant mechanisms maintain and protect intracellular redox homeostasis.2-4 A shift in the balance between oxidants and antioxidants toward oxidation causes DNA mutations, protein oxidation, and lipid peroxidation, which eventually lead to loss of molecular function 1,2,5 and contribute to the pathogenesis of human diseases, including aging and cancer. 3The p53 protein has been proposed as a critical regulator of intracellular ROS levels. Upon activation following DNA damage, p53 can activate several genes that result in increased ROS generation, which contributes to the induction of apoptosis in cells with unrepaired DNA damage.6-10 The induction of apoptosis is central to the tumor-suppressive activity of p53. 11,12 By using the serial analysis of gene expression technique to evaluate the patterns of gene expression following p53 expression, a series of p53-inducible genes (PIG genes) have been identified that are predicted to encode proteins that could generate ROS. 8 Of particular interest is p53-inducible gene 3 (PIG3), which shares sequence similarity with NADPH-quinine oxidoreductase, and is induced by p53 before the onset of apoptosis and contributes to ROS generation.8 Thus, PIG3 is believed to be one of the major factors involved in p53-induced apoptosis through ROS generation. This was the first clear connection between p53 and ROS generation, but the molecular mechanisms of PIG3-induced ROS generation have not yet been elucidated. Under physiological condition, basal levels of p53 can also upregulate antioxidant genes that function to lower ROS levels, and this antioxidant function of p53 is important in preventing oxidative stress-induced DNA damage and tumor development under low-stress conditions.13-21 Thus, p53 has opposing roles in ...

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Coactivation of the CLOCK–BMAL1 complex by CBP mediates resetting of the circadian clock

Cited by 99 publications

References 63 publications

Vertebrate-like CRYPTOCHROME 2 from monarch regulates circadian transcription via independent repression of CLOCK and BMAL1 activity

Vertebrate-like CRYPTOCHROME 2 from monarch regulates circadian transcription via independent repression of CLOCK and BMAL1 activity

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

The critical role of catalase in prooxidant and antioxidant function of p53

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