CRY

Summary: UniProt-curated localization includes nuclear CRY, consistent with light-driven nuclear translocation.

Reason: Subcellular location evidence indicates CRY accumulates in the nucleus after light perception, supporting nuclear localization.

Summary: UniProt-curated localization includes cytoplasmic CRY.

Reason: CRY is reported in cytoplasm and perinuclear region prior to nuclear translocation, supporting cytoplasmic localization.

Summary: CRY can act as a transcriptional repressor of CLK/CYC-activated clock genes (Collins et al. 2006), but this is a Drosophila-specific secondary role confined to peripheral clocks, NOT the canonical mammalian-type light-independent repression. Drosophila CRY (type I) is mechanistically distinct from mammalian CRY1/2 (type II): the falcon deep research establishes that the best-established / primary function of DmCRY is as a blue-light photoreceptor that triggers light-dependent TIM degradation, whereas light-independent transcriptional repression is the defining role of the type II (mammalian) cryptochromes. The IBA inference (from the phylogenetic family) therefore over-weights a repressor role that, in flies, is non-core and peripheral.

Reason: Genuine but secondary/non-core in Drosophila. Collins et al. (PMID:16527739) show repression of CLK/CYC targets is "confined to peripheral clocks" and does not significantly affect pacemaker-neuron or behavioral rhythms; the core DmCRY function is light input via TIM degradation, not transcriptional repression. Distinct from the mammalian type II cryptochrome repressor role that drives this phylogenetic inference.

Summary: The broad DNA-binding IBA is unresolved for Drosophila CRY.

Reason: PTN000155848 carries GO:0003677 from a mixed photolyase/animal-cryptochrome seed set, and PAINT already prunes GO:0003904 at the animal cryptochrome branch without negating DNA binding itself. PMID:10063806 establishes that Drosophila CRY is not a DNA-repair photolyase, but no cached target experiment directly tests DNA binding.

Summary: CRY regulates expression of CLK/CYC target genes, consistent with circadian regulation of gene expression.

Reason: Repression of clock-controlled transcription by CRY supports circadian regulation of gene expression.

Summary: Loss of CRY disrupts synchronization to light-dark cycles, indicating a role in photoperiod entrainment. The falcon deep research details the canonical mechanism: light-activated CRY binds TIM and triggers TIM degradation via recruitment of the E3 ubiquitin ligase Jetlag (JET)/CUL1, leading to TIM ubiquitination and proteasomal degradation, thereby resetting the PER/TIM negative arm and entraining behavioral rhythms. This is the core, best-established DmCRY function.

Reason: Core biological process. CRY is the primary photoreceptor for entrainment of the fly circadian clock and acts by light-dependent TIM degradation.

Summary: CRY binds FAD as the principal blue-light chromophore/cofactor in the photolyase homology region (PHR). The falcon deep research notes that FAD binding is both photochemical (it is the chromophore that absorbs blue light) and a structural requirement for CRY to reach a signaling-competent native fold.

Reason: Core molecular function. UniProt-curated cofactor annotations specify one FAD per subunit, and FAD binding is essential for both photoreception and folding.

Summary: CRY binds a flavin adenine dinucleotide cofactor, supporting nucleotide binding.

Reason: FAD is a nucleotide cofactor; the term is generic but consistent with known cofactor binding.

Summary: UniProt-curated localization includes nuclear CRY.

Reason: Subcellular location annotations indicate nuclear accumulation after light perception.

Summary: UniProt-curated localization includes cytoplasmic CRY.

Reason: CRY localizes to cytoplasm and perinuclear region prior to nuclear translocation.

Summary: CRY expression and function are light regulated, supporting a response to light stimulus.

Reason: Light-regulated expression and photoreceptor function indicate response to light stimulus.

Summary: CRY is a blue-light-dependent photoreceptor in the circadian system. The falcon deep research establishes that this is the best-established/core function of DmCRY: blue light absorbed by FAD drives photoreduction via a Trp triad/tetrad, producing a conformational change (CTT undocking) that enables light-dependent TIM binding and JET-dependent TIM degradation, resetting the circadian oscillator.

Reason: UniProt function description explicitly identifies CRY as a blue-light-dependent regulator in the circadian loop; falcon synthesis confirms photoreceptor activity as the core molecular function.

Summary: CRY accumulates in the perinuclear region before nuclear translocation.

Reason: The perinuclear accumulation is documented as part of CRY light-dependent trafficking.

Summary: CRY functions within the circadian feedback loop, supporting a rhythmic process annotation.

Reason: CRY is a blue-light-dependent regulator in the circadian feedback loop.

Summary: The cited study is focused on circadian network/photoperiod effects and does not present direct CRY binding assays; light-dependent CRY-TIM interaction is documented elsewhere.

Reason: Generic protein binding is uninformative, and the PMID cited does not provide direct binding evidence for CRY. Removing this annotation does not dispute the specific CRY-TIM interaction documented elsewhere.

Summary: CRY can be detected in cytoplasm as well as nucleus.

Reason: Cytoplasmic accumulation is documented in studies of CRY localization; nuclear localization does not exclude cytosolic presence.

Summary: CRY acts as a circadian photoreceptor interacting with core clock components, supporting a role in circadian rhythm.

Reason: The paper explicitly describes CRY as a circadian photoreceptor acting via core clock components, consistent with circadian rhythm involvement.

Summary: CRY mediates light input to circadian oscillators in brain and peripheral tissues, supporting circadian rhythm function.

Reason: The abstract states CRY acts as a photoreceptor mediating light input to circadian oscillators, indicating a role in circadian rhythms.

Summary: The cryb mutation identifies cryptochrome as a circadian photoreceptor, consistent with circadian rhythm involvement.

Reason: Genetic evidence from cryb mutants establishes cryptochrome as a circadian photoreceptor in Drosophila.

Summary: CRY is described as a circadian photoreceptor acting via light-dependent interactions with core clock components.

Reason: The cited study explicitly characterizes CRY as a circadian photoreceptor, supporting photoreceptor activity.

Summary: CRY is a major contributor to circadian rhythm resetting and photosensitivity, supporting circadian rhythm involvement.

Reason: The abstract directly links CRY to circadian rhythm resetting, which is central to circadian rhythm processes.

Summary: CRY mediates blue-light-evoked neuronal responses in pacemaker neurons, supporting a response to blue light.

Reason: Blue-light responsiveness is explicitly reported for CRY in pacemaker neurons; the original study supports CRY as a photosensitive cryptochrome.

Summary: Genetic interaction data support CRY contributions to photoentrainment and synchronization to light-dark cycles.

Reason: The cited study reports altered synchronization in blue light and stronger effects when cryptochrome-based light input is absent; additional evidence shows cry loss affects photoentrainment.

Summary: CRY contributes to circadian clock regulation and acts as a transcriptional repressor of clock-controlled genes.

Reason: Photoentrainment phenotypes in cry mutants support circadian regulation, and CRY represses CLK/CYC-driven transcription.

Summary: Genetic interaction data link CRY to circadian regulation and transcriptional repression.

Reason: cry-dependent photoentrainment plus CRY transcriptional repression supports circadian regulation of gene expression.

Summary: CRY contributes to photoentrainment of the circadian clock.

Reason: Loss of cry impairs photoentrainment, especially when combined with loss of rh7.

Summary: Genetic interaction evidence supports CRY-dependent photoentrainment.

Reason: Combined loss of cry and rh7 causes strong defects in photoentrainment.

Summary: CRY affects circadian behavioral outputs via photoentrainment pathways.

Reason: cry loss disrupts photoentrainment and alters behavioral responses to light cycles.

Summary: Genetic interaction between cry and rh7 affects circadian behavioral entrainment.

Reason: Combined mutations show profound behavioral photoentrainment defects.

Summary: CRY mediates cellular light responses in pacemaker neurons.

Reason: Light-evoked neuronal responses depend on CRY, supporting cellular response to light stimulus.

Summary: Reactome places CRY in nucleoplasm during circadian signaling.

Reason: UniProt subcellular location evidence includes nuclear CRY.

Summary: Reactome places CRY in nucleoplasm during clock-regulatory steps.

Reason: Nuclear localization of CRY is documented in curated UniProt annotations.

Summary: Reactome annotates CRY in nucleoplasm for TIM-related steps.

Reason: CRY translocates to the nucleus after light perception.

Summary: Reactome assigns CRY to nucleoplasm, consistent with light-induced nuclear localization.

Reason: Curated localization places CRY in the nucleus.

Summary: Reactome assigns CRY to cytosol in light-input pathway steps.

Reason: Cytosolic localization of CRY is supported by UniProt curated evidence.

Summary: Reactome assigns CRY to cytosol during TIM-related interactions.

Reason: Cytoplasmic localization is curated for CRY.

Summary: Reactome assigns CRY to cytosol during degradation steps.

Reason: CRY is documented in cytosolic compartments before nuclear translocation.

Summary: Reactome assigns CRY to cytosol in ubiquitination steps.

Reason: Cytosolic localization of CRY is supported by curated UniProt evidence.

Summary: Reactome assigns CRY to cytosol for phosphorylation steps.

Reason: CRY is documented in cytosol/perinuclear regions prior to nuclear translocation.

Summary: Disruption of CRY rhythms by nocturnal light affects sleep regulation.

Reason: Light interruption dampens CRY rhythms and impacts sleep, indicating CRY involvement in circadian sleep/wake regulation.

Summary: TIM binds dCRY in light, but the generic protein-binding term is uninformative.

Reason: The paper supports specific CRY-TIM interaction, but generic GO:0005515 does not identify CRY's light-input molecular function.

Summary: CRY contributes to light synchronization of the circadian clock.

Reason: The study notes that cryptochrome in brain clock neurons contributes to clock synchronization.

Summary: Genetic data in the context of light synchronization support CRY-dependent photoentrainment.

Reason: Cryptochrome contributes to clock synchronization alongside visual photoreceptors.

Summary: dCRY is a FAD-dependent photoreceptor.

Reason: Structural analysis identifies dCRY as FAD-dependent, supporting FAD binding.

Summary: CRY mediates light-dependent magnetoreception. The falcon deep research frames this as a non-canonical, tissue-dependent CRY function: cry mutants lose magnetic-field- dependent behaviors, with proposed radical-pair photochemistry tied to flavin redox.

Reason: Genuine but non-core. Magnetosensitivity is a proposed/secondary CRY function relative to the canonical circadian photoreceptor / TIM-degradation role, and the underlying radical-pair mechanism remains a hypothesis.

Summary: CRY is required for light-dependent responses to magnetic fields. Per falcon, this is a non-canonical CRY function relative to the core circadian photoreceptor role.

Reason: CRY-dependent magnetosensory responses under UV-A/blue light are genuine but secondary to the core circadian photoreceptor / TIM-degradation function.

Summary: CRY is a blue-light photoreceptor that lacks photolyase activity.

Reason: The study characterizes CRY as a blue-light photoreceptor, supporting a role in blue-light signaling.

Summary: CRY is a key component for preferential entrainment to light.

Reason: The study shows CRY-positive neurons preferentially entrain to light cycles.

Summary: CRY participates in light synchronization of circadian rhythms.

Reason: CRY is required for light-driven entrainment of circadian rhythms in clock neurons.

Summary: The CRY-TIM interaction is real, but generic protein binding is uninformative.

Reason: The evidence supports specific light-dependent CRY-TIM interaction rather than an informative generic protein-binding molecular function.

Summary: CRY is necessary for light-dependent magnetosensitive responses. Per falcon, this is a non-canonical CRY function relative to the core circadian photoreceptor role.

Reason: Cry-deficient flies lack magnetic responses under light, but magnetosensitivity is a secondary function relative to the core circadian photoreceptor / TIM-degradation role.

Summary: CRY mediates light input that resets the circadian oscillator. The falcon deep research adds mechanistic detail: TIM then associates with CRY and JET/CUL1, leading to TIM ubiquitination and proteasomal degradation; a 2023 cryo-EM structure shows TIM inserts its N-terminus into the CRY flavin pocket, replacing the autoinhibitory CTT.

Reason: Light-activated CRY binding to TIM promotes degradation and clock resetting, supporting entrainment. Core biological process.

Summary: CRY-dependent magnetic sensitivity of the circadian clock supports magnetoreception. Per falcon, this is a non-canonical, tissue-dependent CRY function relative to the core circadian photoreceptor / TIM-degradation role.

Reason: Magnetic field effects on the clock are light- and CRY-dependent, but magnetosensitivity is a secondary/proposed function, not the core circadian photoreceptor role.

Summary: CRY localizes to the nucleus in light/dark conditions.

Reason: Independent evidence shows nuclear accumulation of CRY in brain neurons.

Summary: CRY localizes to cytoplasm in brain neurons.

Reason: Independent evidence shows cytoplasmic accumulation of CRY in light/dark conditions.

Summary: CRY lacks DNA photolyase activity (negated).

Reason: Recombinant CRY does not show photolyase activity for CPD or 6-4 photoproducts.

Summary: CRY interacts with PER in a light-dependent manner, but the generic binding term is uninformative.

Reason: The evidence supports a specific CRY-PER interaction rather than nonspecific protein binding; removing generic GO:0005515 does not dispute the reported interaction.

Summary: CRY is described as a circadian photoreceptor.

Reason: The study explicitly characterizes CRY as a circadian photoreceptor acting via core clock components.

Summary: Cryptochromes function as blue-light signaling receptors.

Reason: The study describes cryptochromes as flavoprotein blue-light signaling receptors.

Summary: CRY is a blue-light photoreceptor. The falcon deep research confirms this as the core molecular function: DmCRY is a Drosophila-type/type I cryptochrome that functions primarily as a blue-light photoreceptor for circadian clock entrainment, mechanistically distinct from the light-independent mammalian-type (type II) cryptochromes.

Reason: Recombinant CRY lacks photolyase activity and is characterized as a blue-light photoreceptor; this is the core molecular function.

Summary: DCry is identified as a candidate blue-light photoreceptor in Drosophila.

Reason: The study identifies DCry as a blue-light photoreceptor linked to circadian entrainment.

Summary: dCRY functions as a blue-light photoreceptor.

Reason: The study describes dCRY as a blue light photoreceptor involved in clock synchronization.

Summary: CRY contributes to photosensitivity in the circadian system.

Reason: The study links CRY to circadian photosensitivity and light-dependent resetting.

Summary: DCry dosage affects blue-light resetting of circadian locomotor rhythms.

Reason: Changes in DCry gene dosage alter blue-light resetting responses.

Summary: dCRY participates in synchronization of the circadian clock to light-dark cycles.

Reason: The study links dCRY photoreceptor function to circadian clock synchronization.

Summary: CRY contributes to circadian rhythm resetting.

Reason: The study identifies CRY as a major contributor to circadian rhythm resetting and photosensitivity.

Summary: cryb mutants show impaired synchronization to light-dark cycles.

Reason: Genetic loss of CRY affects circadian light synchronization, supporting regulation of circadian rhythm.

Summary: Collins et al. directly demonstrate that Drosophila CRY can repress CLK/CYC-driven transcription, but the effect is "confined to peripheral clocks" and does not significantly affect pacemaker-neuron molecular or behavioral rhythms. This is a genuine but secondary role; the falcon deep research frames the primary/best-established DmCRY function as the blue-light photoreceptor that triggers light-dependent TIM degradation, mechanistically distinct from the mammalian type II repressor role.

Reason: Direct experimental evidence (IMP) for repressor activity is solid, but it is a peripheral-clock-specific, non-core function in Drosophila. The canonical core function is light input via TIM degradation, not transcriptional repression.

Summary: Recombinant CRY binds a flavin adenine dinucleotide chromophore.

Reason: The study reports FAD as a chromophore in purified CRY.

Summary: dCRY contains FAD as a bound cofactor.

Reason: Biochemical analysis shows FAD(ox) in purified dCRY.

Summary: Light induces redox changes in flavin bound to CRY.

Reason: Photoreduction of bound flavin implies FAD binding.

Summary: Light-dependent magnetosensitivity requires CRY, indicating light detection linked to magnetoreception. Per falcon, this is a non-canonical CRY function relative to the core circadian photoreceptor role.

Reason: CRY is necessary for light-dependent magnetic responses, but this magnetosensory detection is secondary to the core circadian photoreceptor / TIM-degradation function.

Summary: CRY contributes to regulation of circadian rhythm, and this study highlights light-responsive pacemaker neuron behavior.

Reason: Pacemaker neuron light responses are consistent with CRY-dependent circadian regulation supported by additional literature.

Summary: The study supports CRY as a circadian photoreceptor, but phototransduction is broader than demonstrated.

Reason: Evidence supports photoreceptor activity, not a complete phototransduction cascade annotation.

Proposed replacements: photoreceptor activity

Summary: Drosophila CRY is a circadian photoreceptor.

Reason: The paper explicitly describes Drosophila CRY as a circadian photoreceptor.

Summary: Type 1 CRYs contain FAD when purified.

Reason: The study reports FAD in purified insect CRYs including Drosophila.

Summary: CRY mediates photic input to the circadian clock.

Reason: The study identifies cryptochrome as a photopigment in brain clock neurons affecting light responses.

Summary: CRY-dependent light input affects behavioral rhythmicity.

Reason: The study reports maintenance of behavioral rhythmicity under constant light in CRY pathway variants, consistent with locomotor rhythm modulation.

Summary: Light entrainment involves light-induced TIM degradation in a CRY-dependent pathway.

Reason: The study links light entrainment to TIM degradation and notes interaction with CRY pathway components.

Summary: CRY-containing complexes reside primarily in the nucleus after light perception.

Reason: The study describes nuclear localization of CRY/PER/TIM complexes after light.

Summary: Light-activated CRY regulates circadian photoresponses.

Reason: The study directly links CRY activation by light to circadian photoresponses.

Summary: DCry is an extraretinal blue-light photoreceptor implicated in circadian photoresponses.

Reason: The study identifies DCry as a blue-light photoreceptor in brain clock neurons.

Summary: Light entrainment involves the eyelet and cryptochrome pathways.

Reason: The study reports that eyelet together with cryptochrome mediates phase delays in entrainment.

Summary: cry mutants show altered geotaxis scores, supporting a role in gravitaxis. This is a pleiotropic behavioral effect rather than the core circadian photoreceptor function; the falcon deep research does not feature gravitaxis among CRY's well-established roles.

Reason: The full text reports that homozygous cry mutants significantly increase geotaxis scores, but this is a downstream/pleiotropic behavioral phenotype, not a core function.

Summary: CRY activation by light affects circadian photoresponses and entrainment.

Reason: Light-activated CRY regulates photoresponses consistent with photoperiod entrainment.

Summary: Light entraining signals require CRY-dependent pathways.

Reason: The study states that cryptochrome-mediated pathways provide entraining light signals to the clock.

Summary: CRY and TIM directly interact in a light-dependent complex, but GO:0005515 is uninformative.

Reason: PMID:10417378 directly supports CRY-TIM protein binding, and this UniProtKB:P49021 row is the same partner assertion as the existing FlyBase-supported IPI row from the same paper. The interaction is real and central to CRY's light-input function; only the uninformative generic GO:0005515 annotation should be removed.

Summary: The cryb mutation impairs circadian light responses.

Reason: This genetic-interaction row is broad but correct: cryb removes CRY-dependent circadian photoreception, causing poor light-dark synchronization in blinded or high-reset-demand backgrounds and eliminating responses to brief light pulses.

Summary: CRY contributes to photoperiod entrainment together with Rh5/Rh6 and NORPA-independent visual inputs.

Reason: The Rh5/Rh6 study tested compound-eye and CRY pathways in clock synchronization. This row is a valid genetic-interaction assertion for photoperiod entrainment, with a broader WITH/FROM combination than the pre-existing Rh5/Rh6 row.

Summary: CRY contributes to Rh5/NORPA-dependent clock synchronization.

Reason: The IGI source row records a subset of the Rh5/Rh6/NORPA genetic combinations assayed for clock synchronization. The cited abstract explicitly establishes that visual photoreceptors and CRY both contribute to Drosophila light synchronization.

Summary: CRY contributes to Rh6/NORPA-dependent clock synchronization.

Reason: The IGI source row records a subset of the Rh5/Rh6/NORPA genetic combinations assayed for clock synchronization. Rh6 is one of the visual photopigments whose clock-synchronization contribution was tested in a norpA(P41) background alongside CRY-mediated input.

Summary: CRY contributes to NORPA-independent photoperiod entrainment.

Reason: This source row captures the CRY/NORPA genetic background used to separate brain CRY photoreception from canonical retinal phospholipase C-beta signaling. It is a broad but valid entrainment annotation.