Roles of the Two
            <i>Drosophila</i>
            CRYPTOCHROME Structural Domains in Circadian Photoreception

Busza, Ania; Emery-Le, Myai; Rosbash, Michael; Emery, Patrick

doi:10.1126/science.1096973

Cited by 267 publications

(361 citation statements)

References 30 publications

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“…Although not definitive, these results support earlier claims that the photoreceptors may directly (or indirectly) synapse with the l-LN v s (40). As stated above, these molecular and proposed functional differences between s-and l-LN v s may also contribute to explaining the loss of light responsiveness in cry b mutant flies, which are blind to constant light and brief light pulses, despite retaining light input from the canonical visual transduction pathway (7,11,41,42). Thus CRYPTOCHROME, aside from being a photoreceptor in its own right, also appears to control a gateway for rhodopsin-mediated light input into the clock.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Cryptochrome partially restores circadian rhythmicity to the arrhythmic period mutant of Drosophila

Collins

Dissel

Gaten

et al. 2005

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

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The Drosophila melanogaster circadian clock is generated by interlocked feedback loops, and null mutations in core genes such as period and timeless generate behavioral arrhythmicity in constant darkness. In light-dark cycles, the elevation in locomotor activity that usually anticipates the light on or off signals is severely compromised in these mutants. Light transduction pathways mediated by the rhodopsins and the dedicated circadian blue light photoreceptor cryptochrome are also critical in providing the circadian clock with entraining light signals from the environment. The cry b mutation reduces the light sensitivity of the fly's clock, yet locomotor activity rhythms in constant darkness or light-dark cycles are relatively normal, because the rhodopsins compensate for the lack of cryptochrome function. Remarkably, when we combined a period-null mutation with cry b , circadian rhythmicity in locomotor behavior in light-dark cycles, as measured by a number of different criteria, was restored. This effect was significantly reduced in timeless-null mutant backgrounds. Circadian rhythmicity in constant darkness was not restored, and TIM protein did not exhibit oscillations in level or localize to the nuclei of brain neurons known to be essential for circadian locomotor activity. Therefore, we have uncovered residual rhythmicity in the absence of period gene function that may be mediated by a previously undescribed period-independent role for timeless in the Drosophila circadian pacemaker. Although we do not yet have a molecular correlate for these apparently iconoclastic observations, we provide a systems explanation for these results based on differential sensitivities of subsets of circadian pacemaker neurons to light.anticipation ͉ phase shift ͉ oscillator ͉ hourglass ͉ timeless T he PERIOD (PER) and TIMELESS (TIM) proteins are core components of the negative feedback loop that drives circadian oscillations in Drosophila. TIM stabilizes PER, and the PER and TIM proteins cooperate in nuclear entry and retention in key pacemaker cells at night (1). TIM degrades rapidly in response to light, releasing PER to repress per and tim transcription (1). D. melanogaster individuals carrying the null mutation per 01 display arrhythmic locomotor activity under constant darkness (DD), whereas in light-dark (LD) cycles, their locomotor activity is elevated under illumination and reduced in darkness, reflecting the ''masking'' effect of light (2, 3). Another mutation in the gene encoding the blue-light photoreceptor cryptochrome, cry b , gives attenuated light responses in a circadian context (4-7), but normal circadian locomotor behavior in 24-h LD cycles. As part of another study of seasonal behavioral responses to temperature and light effected via changes in per 3Ј splicing, we generated a per 01 ; cry b double mutant (8). We noted that a modest cycle in wild-type per 3Ј splicing in LD cycles at 29°C was exaggerated in per 01 and cry b mutants, yet in the double mutant, the amplitude of the splicing reverted back to ap...

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Section: Discussionmentioning

confidence: 99%

Disruption of Cryptochrome partially restores circadian rhythmicity to the arrhythmic period mutant of Drosophila

Collins

Dissel

Gaten

et al. 2005

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

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“…However, the actual action spectrum of hypocotyl growth inhibition in Arabidopsis is quite flat in the 390-480-nm range (Ahmad et al 2002). Finally, DmCry missing the carboxy-terminal extension is capable of photoreception and phototransduction, suggesting that at least in some CRYs, the carboxy-terminal domain is not necessary for photosignaling (Busza et al 2004). …”

Section: Functional Properties Of Animal Cryptochrome Cryptochrome Phmentioning

confidence: 99%

Structure and Function of Animal Cryptochromes

Öztürk

Song²,

Özgür³

et al. 2007

Cold Spring Harbor Symposia on Quantitative Biology

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Cryptochrome (CRY) is a photolyase-like flavoprotein with no DNA-repair activity but with known or presumed blue-light receptor function. Animal CRYs have DNA-binding and autokinase activities, and their flavin cofactor is reduced by photoinduced electron transfer. In Drosophila, CRY is a major circadian photoreceptor, and in mammals, the two CRY proteins are core components of the molecular clock and potential circadian photoreceptors. In mammals, CRYs participate in cell cycle regulation and the cellular response to DNA damage by controlling the expression of some cell cycle genes and by directly interacting with checkpoint proteins. in response to blue light (Koornneef et al. 1980), was isolated and sequenced, it revealed high sequence homology with Escherichia coli photolyase, and hence, it was in retrospect, correctly speculated that HY4 encoded a blue light photoreceptor and not a signal transducer involved in blue light response (Ahmad and Cashmore 1993). Later, this protein was named cryptochrome 1 (Lin et al. 1995, and a second Arabidopsis protein that has high homology with CRY1 identified by genomics was named CRY2 . The role of CRY in Arabidopsis growth (CRY1) and differentiation (CRY2) was well established by 1995 (see Guo et al. 1998). However, as late as 1997, it was thought that CRY had no role in circadian photoreception in plants (Millar and Kay 1997).The first report implicating CRY in the circadian clock of any organism, plant or animal, came about from the study of DNA repair, in particular, the repair of UV damage in humans by photolyase. This issue had been controversial for nearly 25 years when Li et al. (1993) conducted an exhaustive study with a highly specific and sensitive assay, concluding that humans, like all placental mammals, lacked photolyase (Li et al. 1993). However, a 1995 release of a human expressed sequence tag (EST) list contained a "photolyase ortholog" entry (Adams et al. 1995). In light of this finding and the discovery of a photolyase in Drosophila and rattlesnake (Todo et al. 1993Kim et al. 1996) that repairs the minor UV-induced lesion, the (6-4) photoproduct, in contrast to the classic photolyase that repairs cyclobutane pyrimidine dimers (CPDs), the earlier conclusion regarding the lack of photolyase in humans needed reevaluation. This was done by Hsu et al. (1996) who, in addition to the "photolyase ortholog" in public databases, discovered a second human photolyase gene. Human cells expressing both genes and recombinant proteins encoded by both genes were tested for CPD and (6-4) photolyase activities and were found to lack both. Moreover, the proteins encoded by these genes, like most photolyases (Johnson et al. 1988) and Arabidopsis CRY (Lin et al. 1995; Malhorta et al. 1995), contained FAD (flavin-adenine dinucleotide) and a pterin cofactor. Therefore, it was concluded that these proteins were not repair enzymes but that, like Arabidopsis CRYs, they performed non-repair-related blue light functions and were named human CRY1 and 2 (Hsu et al. 1996). In humans ...

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“…5A). Although cry b is a loss-of-function mutant of cry, it leaks out a low level of its encoded protein (32). To exclude the possibility that leaking proteins participate in driving the oscillation for the cuticle deposition rhythm in cry b , we tested the cuticle deposition under DD in another cry mutant, cry OUT , in which no CRY protein is detected by immunohistochemistry (33).…”

Section: Regulation Of Cuticle Deposition By a Circadian Oscillatormentioning

confidence: 99%

Peripheral circadian clock for the cuticle deposition rhythm in Drosophila melanogaster

Ito

Goto

Shiga

et al. 2008

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

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Insect endocuticle thickens after adult emergence by daily alternating deposition of two chitin layers with different orientation. Although the cuticle deposition rhythm is known to be controlled by a circadian clock in many insects, the site of the driving clock, the photoreceptor for entrainment, and the oscillatory mechanism remain elusive. Here, we show that the cuticle deposition rhythm is regulated by a peripheral oscillator in the epidermis in Drosophila melanogaster. Free-running and entrainment experiments in vitro reveal that the oscillator for the cuticle deposition rhythm is independent of the central clock in the brain driving the locomotor rhythms. The cuticle deposition rhythm is absent in null and dominant-negative mutants of clock genes (i.e., period, timeless, cycle, and Clock), indicating that this oscillator is composed of the same clock genes as the central clock. Entrainment experiments with monochromatic light-dark cycles and cry b flies reveal that a blue light-absorbing photoreceptor, cryptochrome (CRY), acts as a photoreceptor pigment for the entrainment of the cuticle deposition rhythm. Unlike other peripheral rhythms in D. melanogaster, the cuticle deposition rhythm persisted in cry b and cry OUT mutant flies, indicating that CRY does not play a core role in the rhythm generation in the epidermal oscillator.circadian rhythm ͉ clock genes ͉ cryptochrome ͉ entrainment ͉ epidermal cell C ircadian clocks control daily rhythms at the molecular, physiological, and behavioral levels. Like most organisms, the central circadian oscillator controlling the locomotor activity rhythm in Drosophila is proposed to consist of molecular feedback loops. The feedback loops comprise several core clock genes, such as period (per), timeless (tim), Clock (Clk), and cycle (cyc) (1). These genes encode PER, TIM, CLK, and CYC proteins, respectively, and loss-of-function or dominant-negative mutations in these genes result in loss of normal circadian rhythmicity (2-5). CLK and CYC form a heterodimer to activate transcription of per and tim (2, 4, 6). PER and TIM form another heterodimer, are transferred into the nucleus, and then inactivate the transcriptional activity of the CLK/CYC heterodimer (6). The feedback loops are entrained and reset by the lightinduced degradation of TIM mediated by a photoreceptor pigment, cryptochrome (CRY) (7-10).In addition to the central oscillator, peripheral oscillators exist in many tissues, including the compound eyes, antennae, wings, legs, and Malpighian tubules in adults and the ring gland in pupae (11)(12)(13)(14). These oscillators are self-sustained and directly light-entrainable even in vitro (11-13). In addition, the oscillators are clearly independent of the central circadian oscillator(s) in the brain (15, 16). Previous reports revealed that the peripheral oscillator shares the same genes with the central clock in the brain (12, 17). However, there is a remarkable difference that, in the peripheral oscillator, CRY functions as a core component besides a photorecepto...

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Roles of the Two Drosophila CRYPTOCHROME Structural Domains in Circadian Photoreception

Cited by 267 publications

References 30 publications

Disruption of Cryptochrome partially restores circadian rhythmicity to the arrhythmic period mutant of Drosophila

Disruption of Cryptochrome partially restores circadian rhythmicity to the arrhythmic period mutant of Drosophila

Structure and Function of Animal Cryptochromes

Peripheral circadian clock for the cuticle deposition rhythm in Drosophila melanogaster

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