A central role for ubiquitination within a circadian clock protein modification code

Stojkovic, Katarina; Wing, Simon S.; Cermakian, Nicolas

doi:10.3389/fnmol.2014.00069

Cited by 86 publications

(86 citation statements)

References 58 publications

(93 reference statements)

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“…We propose that without Siah2, RevErb proteins can repress their target genes longer, thereby delaying the activation of these target genes within the clockwork and the start of the next circadian cycle. This same concept explains why loss of rhythmic PER1/2 and CRY1/2 degradation slows circadian clock function (6,7). Consistent with this idea, Ueda and coworkers have shown that strengthening the binding of RevErbα to its response element within the Cry1 promoter can prolong the repression of Cry1 expression and lengthen circadian periods (39).…”

Section: Discussionmentioning

confidence: 75%

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Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock

DeBruyne

Baggs

Sato

et al. 2015

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

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Regulated degradation of proteins by the proteasome is often critical to their function in dynamic cellular pathways. The molecular clock underlying mammalian circadian rhythms relies on the rhythmic expression and degradation of its core components. However, because the tools available for identifying the mechanisms underlying the degradation of a specific protein are limited, the mechanisms regulating clock protein degradation are only beginning to be elucidated. Here we describe a cell-based functional screening approach designed to quickly identify the ubiquitin E3 ligases that induce the degradation of potentially any protein of interest. We screened the nuclear hormone receptor RevErbα (Nr1d1), a key constituent of the mammalian circadian clock, for E3 ligases that regulate its stability and found Seven in absentia2 (Siah2) to be a key regulator of RevErbα stability. Previously implicated in hypoxia signaling, Siah2 overexpression destabilizes RevErbα/β, and siRNA depletion of Siah2 stabilizes endogenous RevErbα. Moreover, Siah2 depletion delays circadian degradation of RevErbα and lengthens period length. These results demonstrate the utility of functional screening approaches for identifying regulators of protein stability and reveal Siah2 as a previously unidentified circadian clockwork regulator that mediates circadian RevErbα turnover.circadian clock | RevErbα/Nr1d1 | Siah2 | ubiquitin ligase screen C ircadian rhythms originate from intracellular clocks that drive the rhythmic expression of thousands of genes that ultimately manifests in daily rhythms of physiology and behavior. In mammals, the core circadian clock mechanism is composed of two interlocked transcriptional negative feedback loops (1, 2). In the primary loop, the bHLH-PAS domain containing transcriptional activators Bmal1 (Arntl) and Clock (or its ortholog Npas2) form a DNA-binding heterodimer that drives expression of the Per1/2/3 and Cry1/2 genes. Their protein products ultimately feed back to repress CLOCK:BMAL1 activity. This loop also drives rhythmic expression of the nuclear hormone receptors RevErbα and RevErbβ (Nr1d1 and Nr1d2, respectively), which in turn rhythmically repress expression of Bmal1, Clock, and Npas2 (3-5). Circadian expression of core clock genes and their regulated protein degradation are essential for maintaining proper timekeeping (6, 7).The ubiquitin-proteasome pathway is responsible for the degradation of nearly all regulated proteins, including circadian clock proteins. Deficits in this process are linked to diseases ranging from cancers to neurodegenerative disorders (8-10). The ubiquitin system requires the activity of three classes of proteins: E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases. E3 ubiquitin ligases are responsible for specifying substrates and facilitating the transfer of ubiquitin directly or indirectly from E2s to the substrate protein being targeted for degradation. There are ∼600 mouse/human genes that encode E3 ligases, and there are thousands...

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Section: Discussionmentioning

confidence: 75%

“…This loop also drives rhythmic expression of the nuclear hormone receptors RevErbα and RevErbβ (Nr1d1 and Nr1d2, respectively), which in turn rhythmically repress expression of Bmal1, Clock, and Npas2 (3)(4)(5). Circadian expression of core clock genes and their regulated protein degradation are essential for maintaining proper timekeeping (6,7).…”

mentioning

confidence: 99%

Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock

DeBruyne

Baggs

Sato

et al. 2015

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

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“…Many studies have found significant correlations between disrupted circadian rhythms and increased risk for certain cancers, including breast cancer (44). Ubiquitination regulates the stability of core clock proteins; thus, it is possible that this protein interacts with core circadian proteins to regulate rhythms in cell growth and differentiation (45). Again, the role of this protein in the human PFC is not clear.…”

Section: Discussionmentioning

confidence: 99%

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Chen

Logan

et al. 2015

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

225

219

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With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.

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“…For the rhythmic expression of clock genes and output (clockcontrolled) genes, both quantity control (amount) and quality control (localization and activity) of the clock proteins are critically important throughout the circadian day. To achieve this rhythmic expression   , clock proteins are precisely controlled by multiple PTMs during the circadian cycle [3][4][5] . Clocks in other organisms, such as Drosophila and Neurospora, have similar feedback loops in which finely tuned PTMs contribute to circadian regulation 3,6 .…”

Section: Instructions For Reviewing Your Article Proofmentioning

confidence: 99%

The intricate dance of post-translational modifications in the rhythm of life

Hirano

Ptáček

2016

Nat Struct Mol Biol

155

141

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A central role for ubiquitination within a circadian clock protein modification code

Cited by 86 publications

References 58 publications

Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock

Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

The intricate dance of post-translational modifications in the rhythm of life

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