A Role for
            <i>Drosophila</i>
            ATX2 in Activation of PER Translation and Circadian Behavior

Zhang, Yong; Ling, Jinli; Yuan, Cong; Dubruille, Raphaëlle; Emery, Patrick

doi:10.1126/science.1234746

Cited by 125 publications

(128 citation statements)

References 40 publications

(42 reference statements)

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“…Bantam seems to have a predominant role but it might not be unique. The presence of this type of regulation is not surprising given the large amount of reports demonstrating the importance of RNA metabolism for circadian timekeeping 28,41,[56][57][58][59][60] .…”

Section: Discussionmentioning

confidence: 99%

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

et al. 2015

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The transcription factor CLOCK (CLK) is essential for the development and maintenance of circadian rhythms in Drosophila. However, little is known about how CLK levels are controlled. Here we show that Clk mRNA is strongly regulated post-transcriptionally through its 3 0 UTR. Flies expressing Clk transgenes without normal 3 0 UTR exhibit variable CLK-driven transcription and circadian behaviour as well as ectopic expression of CLK-target genes in the brain. In these flies, the number of the key circadian neurons differs stochastically between individuals and within the two hemispheres of the same brain. Moreover, flies carrying Clk transgenes with deletions in the binding sites for the miRNA bantam have stochastic number of pacemaker neurons, suggesting that this miRNA mediates the deterministic expression of CLK. Overall our results demonstrate a key role of Clk post-transcriptional control in stabilizing circadian transcription, which is essential for proper development and maintenance of circadian rhythms in Drosophila.

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Section: Discussionmentioning

confidence: 99%

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

et al. 2015

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“…Increasing evidence points to the importance of the circadian clock in controlling mRNA translation, including rhythmic activation of cap-dependent translation factors (6, 7, 28-30), and specific RNA binding proteins that control the translation of core clock genes (31)(32)(33)(34)(35). Although the initiation of translation has long been considered to be the primary control step in translation (36), a growing body of evidence points to translation elongation being regulated (37,38), with phosphorylation and reduction in activity of eEF-2 being a central point in this control.…”

Section: Discussionmentioning

confidence: 99%

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2

Caster

Castillo

Sachs

et al. 2016

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

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The circadian clock has a profound effect on gene regulation, controlling rhythmic transcript accumulation for up to half of expressed genes in eukaryotes. Evidence also exists for clock control of mRNA translation, but the extent and mechanisms for this regulation are not known. In Neurospora crassa, the circadian clock generates daily rhythms in the activation of conserved mitogen-activated protein kinase (MAPK) pathways when cells are grown in constant conditions, including rhythmic activation of the well-characterized p38 osmosensing (OS) MAPK pathway. Rhythmic phosphorylation of the MAPK OS-2 (P-OS-2) leads to temporal control of downstream targets of OS-2. We show that osmotic stress in N. crassa induced the phosphorylation of a eukaryotic elongation factor-2 (eEF-2) kinase, radiation sensitivity complementing kinase-2 (RCK-2), and that RCK-2 is necessary for high-level phosphorylation of eEF-2, a key regulator of translation elongation. The levels of phosphorylated RCK-2 and phosphorylated eEF-2 cycle in abundance in wild-type cells but not in cells deleted for OS-2 or the core clock component FREQUENCY (FRQ). Translation extracts from cells grown in constant conditions show decreased translational activity in the late subjective morning, coincident with the peak in eEF-2 phosphorylation, and rhythmic translation of glutathione S-transferase (GST-3) from constitutive mRNA levels in vivo is dependent on circadian regulation of eEF-2 activity. In contrast, rhythms in phosphorylated eEF-2 levels are not necessary for rhythms in accumulation of the clock protein FRQ, indicating that clock control of eEF-2 activity promotes rhythmic translation of specific mRNAs.C ircadian rhythms are the outward manifestation of an endogenous clock mechanism common to nearly all eukaryotes. Depending on the organism and tissue, nearly half of an organism's expressed genes are under control of the circadian clock at the level of transcription (1-4). However, mounting evidence indicates a role for the clock in controlling posttranscriptional mechanisms (5), including translation initiation (6, 7), whereas clock control of translation elongation has not been investigated.The driver of circadian rhythms in Neurospora crassa is an autoregulatory molecular feedback loop composed of the negative elements FREQUENCY (FRQ) and FRQ RNA-interacting helicase (FRH), which inhibit the activity of the positive elements WHITE COLLAR-1 (WC-1) and WC-2 (8-11). WC-1 and WC-2 heterodimerize to form the white collar complex (WCC), which activates transcription of frequency (frq) (8,12,13) and activates transcription of a large set of downstream target genes important for overt rhythmicity (2, 14). One gene directly controlled by the WCC is os-4, which encodes the mitogen-activated protein kinase kinase kinase (MAPKKK) in the osmotically sensitive (OS) MAPK pathway (15). Rhythmic transcription of os-4 leads to rhythmic accumulation of the phosphorylated active form of the downstream p38-like mitogen-activated protein kinase (MAPK) OS-2 (16). In Sac...

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“…Interestingly, TYF expression appears to be limited to pacemaker circadian neurons (the ventral and dorsal lateral neurons), and PER expression is only reduced in these neurons in tyf mutants [54]. ATAXIN-2 (ATX2), an RNA binding protein involved in several neuronal degenerative diseases in humans, forms a complex with TYF and is required for TYF’s transactivation activity on per [55••,56••] (Figure 2). Through its ability to bind PABP, ATX2 promotes the formation of TYF/PABP complexes.…”

Section: Post-transcriptional Regulationmentioning

confidence: 99%

The molecular ticks of the Drosophila circadian clock

Tataroglu

Emery

2015

Current Opinion in Insect Science

Self Cite

108

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Drosophila is a powerful model to understand the mechanisms underlying circadian rhythms. The Drosophila molecular clock is comprised of transcriptional feedback loops. The expressions of the critical transcriptional activator CLK and its repressors PER and TIM are under tight transcriptional control. However, posttranslational modification of these proteins and regulation of their stability are critical to their function and to the generation of 24-hr period rhythms. We review here recent progress made in our understanding of PER, TIM and CLK posttranslational control. We also review recent studies that are uncovering the importance of novel regulatory mechanisms that affect mRNA stability and translation of circadian pacemaker proteins and their output.

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A Role for Drosophila ATX2 in Activation of PER Translation and Circadian Behavior

Cited by 125 publications

References 40 publications

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2

The molecular ticks of the Drosophila circadian clock

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