DNA damage kinase signaling: checkpoint and repair at 30 years

The EMBO Journal, Год журнала: 2019, Номер 38(18)

Опубликована: Авг. 8, 2019

Язык: Английский

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Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response

Journal of Biological Chemistry, Год журнала: 2021, Номер 297(3), С. 101077 - 101077

Опубликована: Авг. 12, 2021

Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact activity, localization, or stability. To regulate this process, deubiquitinating enzymes (DUBs) counter the signal induced conjugases ligases removing from these substrates. Many DUBs selectively physiological pathways employing conserved mechanisms of bond cleavage. DUB activity highly regulated environments through protein–protein interaction, posttranslational modification, relocalization. The largest family DUBs, cysteine proteases, also sensitive regulation oxidative stress, as reactive oxygen species (ROS) directly modify catalytic required for their enzymatic activity. Current research has implicated human diseases, including various cancers neurodegenerative disorders. Due selectivity functional roles, have become important targets therapeutic development treat conditions. This review will discuss main classes regulatory with particular focus on redox its during stress. When subject ubiquitination arises, most people think canonical pathway ubiquitin-dependent proteasomal targeting. This, however, only represents fraction diversity ubiquitin. small (76 amino acid) eukaryotic that acts modifier (1Watson D.C. Levy W.B. Dixon G.H. Free non-histone trout testis chromatin.Nature. 1978; 276: 196-198Crossref PubMed Google Scholar). very robust diverse where series act coordinated covalently one more molecules form chain (2Komander D. Rape M. code.Annu. Rev. Biochem. 2012; 81: 203-229Crossref Scopus (1845) Scholar, 3Kliza K. Husnjak Resolving complexity networks.Front. Mol. Biosci. 2020; 7: 21Crossref (22) 4Callis J. machinery system.Arabidopsis Book. 2014; 12e0174Crossref Each different chains unique structure, thus providing opportunity single influence numerous pathways, other than degradation, DNA damage repair translation trafficking 5Dittmar G. Winklhofer K.F. Linear chains: Cellular functions strategies detection quantification.Front. Chem. 2019; 915Crossref (9) 6Li W. Ye Y. Polyubiquitin Functions, structures, mechanisms.Cell. Life Sci. 2008; 65: 2397-2406Crossref (168) 7Brinkmann Schell Hoppe T. Kashkar H. Regulation response conjugation.Front. Genet. 2015; 6: 98Crossref (35) 8Clague M.J. Urbe S. Integration cellular membrane traffic systems: Focus deubiquitylases.FEBS 2017; 284: 1753-1766Crossref (21) 9Dougherty S.E. Maduka A.O. Inada Silva G.M. Expanding role translational control.Int. 21: 1151Crossref (12) In removed reversible fashion achieved hydrolases known (10Komander Mechanism, specificity structure deubiquitinases.Subcell 2010; 54: 69-87Crossref 11Mevissen T.E.T. Komander Mechanisms deubiquitinase regulation.Annu. 86: 159-192Crossref (347) 12Reyes-Turcu F.E. Ventii K.H. Wilkinson K.D. roles ubiquitin-specific enzymes.Annu. 2009; 78: 363-397Crossref (967) adaptive nature signaling, frequently utilized function environmental changes stress (13Fang N.N. Zhu Rose A. Wu K.P. Mayor Deubiquitinase degradation misfolded cytosolic proteins upon heat-stress.Nat. Commun. 2016; 12907Crossref (34) 14Li Huang Xu Zhou L. Liang Gao C. Long CYLD negatively regulates high glucose NF-kappaB inflammatory mesangial cells.Biomed. Res. Int. 2017: 3982906Crossref (5) 15Cotto-Rios X.M. Békés Chapman Ueberheide B. T.T. Deubiquitinases target stress.Cell Rep. 2: 1475-1484Abstract Full Text PDF (115) 16Dai F. Lee Zhang Zhuang Yao Xi Xiao Z.D. You Li Su X. Gan BAP1 inhibits ER gene network modulates metabolic response.Proc. Natl. Acad. U. 114: 3192-3197Crossref (48) (Fig. 1), an E1 activating enzyme responsible ATP-dependent manner charging E2 conjugase (17Schulman B.A. Harper J.W. Ubiquitin-like activation enzymes: apex downstream signalling pathways.Nat. Cell Biol. 10: 319-331Crossref (514) then either transfers substrate E3 ligase transfer molecule (18Ye Building at work.Nat. 755-764Crossref (611) former case, brought into proximity associated A number exist (∼40 E2s over 600 E3s humans 12 ∼80 yeast), pairing determines ubiquitinated (19George A.J. Hoffiz Y.C. Charles Mabb A.M. comprehensive atlas mutations neurological disorders.Front. 2018; 9: 29Crossref (45) 20Stewart M.D. Ritterhoff Klevit R.E. Brzovic P.S. More just middle men.Cell 26: 423-440Crossref determining how assembled 21Metzger M.B. Pruneda J.N. Weissman RING-type ligases: Master manipulators ubiquitin-conjugating ubiquitination.Biochim. Biophys. Acta. 1843: 47-60Crossref (313) Protein commonly occurs via isopeptide between C-terminus lysine (22Rechsteiner Ubiquitin-mediated intracellular proteolysis.Annu. 1987; 3: 1-30Crossref Other forms nonlysine rare but exist, peptide bonds N-terminal methionine (M1), thioester residue, hydroxyester serine threonine residue (23McClellan Laugesen S.H. Ellgaard molecular non-lysine ubiquitination.Open 190147Crossref Furthermore, recently been shown be conjugated nonprotein surfaces such lipopolysaccharides (24Otten E.G. Werner E. Crespillo-Casado Boyle K.B. Dharamdasani V. Pathe Santhanam Randow Ubiquitylation lipopolysaccharide RNF213 bacterial infection.Nature. 2021; 594: 111-116Crossref (13) Once first substrate, second round conjugation linking two together (25Nonhoff Ralser Welzel Piccini I. Balzereit Yaspo M.L. Lehrach Krobitsch Ataxin-2 interacts DEAD/H-box RNA helicase DDX6 interferes P-bodies granules.Mol. Cell. 2007; 18: 1385-1396Crossref (230) linked polyubiquitin any seven residues (K6, K11, K27, K29, K33, K48, K63) well group M1 (26Akutsu Dikic Bremm glance.J. 129: 875-880Crossref (217) linkage sites provides archetype, while many can proteasome-dependent some extent, others serve array Proteomics data demonstrate types increase inhibition proteasome, K63-linked does not, suggesting it involved almost exclusively nonproteasomal (27Kim Bennett E.J. Huttlin E.L. Guo Possemato Sowa M.E. Rad R. Rush Comb Gygi S.P. Systematic quantitative assessment ubiquitin-modified proteome.Mol. 2011; 44: 325-340Abstract (1063) 28Xu P. Duong D.M. Seyfried N.T. Cheng Xie Robert Hochstrasser Finley Peng Quantitative proteomics reveals unconventional degradation.Cell. 137: 133-145Abstract (790) topologies may bound recognized distinct generate signals (29Husnjak Ubiquitin-binding proteins: Decoders ubiquitin-mediated functions.Annu. 291-322Crossref (459) Additionally, both homotypic chains, each same (e.g., K48-linked chains) heterotypic multiple (30Yau increasing code.Nat. 579-586Crossref produce branched themselves PTMs phosphorylation SUMOylation, further expanding possibilities 31Ohtake Tsuchiya emerging architecture.J. 161: 125-133PubMed While widely studied, significant advancement study responsive removal occurred. Humans encode ∼100 disassembling thereby signals, recycling (32Komander Clague Breaking Structure deubiquitinases.Nat. 550-563Crossref (1276) done cleaving monomers distal end entire breaking proximal (12Reyes-Turcu Similar conjugases, usually specific they bind (11Mevissen Since direct antagonists conjugation, results switch-like system levels therefore determined competing systems, expression, subcellular location, controlled interactions modifications (PTMs) 2) (33Sahtoe D.D. Sixma T.K. Layers regulation.Trends 40: 456-467Abstract (87) 34Zheng N. Shabek Structure, function, 129-157Crossref (415) E2s, E3s, respond cues induce prioritization generation (3Kliza stresses, regulation, those result active site large (35Lee J.G. Baek Soetandyo Reversible inactivation deubiquitinases vitro cells.Nat. 2013; 4: 1568Crossref (105) ability makes them interesting therapeutics. Indeed, dysregulation malfunction disorders, resulting aberrant within cell (36Kowalski J.R. Juo synaptic nervous diseases.Neural Plast. 2012: 892749Crossref (37) 37Fraile J.M. Quesada Rodriguez Freije Lopez-Otin cancer: New options.Oncogene. 31: 2373-2388Crossref (292) importance, small-molecule inhibitors selective being developed goal utilization treatments diseases (38Harrigan J.A. Jacq Martin N.M. Jackson Deubiquitylating drug discovery: Emerging opportunities.Nat. Drug Discov. 17: 57-78Crossref (241) Recent insights importance combined drugs potential, marked newly burgeoning field provided directions future studies come. As we learn about processes, gain emphasis signals. addition regulating generated essential maintain supply down synthesized fusion 1) (39Pickart C.M. I.A. carboxyl-terminal hydrolase amides.J. 1985; 260: 7903-7910Abstract 40Hanna Meides D.P. induces altered proteasome composition.Cell. 747-759Abstract (0) Constant maintenance free pool necessary homeostasis required, environment biomolecular incurred (41Park C.W. Ryu K.Y. dynamics homeostasis.BMB 47: 475-482Crossref (64) section highlight play cells. Table 1 summarizes class, family, all specifically discussed review.Table 1List mentioned classificationsDUB (∗known redox-sensitive)ClassFamilyKnown ub specificityKnown affectedA20∗Cysteine proteaseoutK63NF-κB (157Shembade Harhaj E.W. A20 deubiquitinase.Cell. Immunol. 123-130Crossref (123) Scholar)AMSHMetalloproteaseJAMM/MPN+K63Endocytosis/sorting (249Davies Paul L.N. Das Mechanism recruitment endosome-associated AMSH.Biochemistry. 52: 7818-7829Crossref (24) Scholar)AMSH-LPMetalloproteaseJAMM/MPN+K63Endocytosis/sorting Scholar)ATXN3Cysteine proteaseMJDK48, K63Protein (250Durcan T.M. Kontogiannea Thorarinsdottir Fallon Williams Djarmati Fantaneanu Paulson H.L. Fon E.A. Machado-Joseph disease-associated mutant ataxin-3 parkin stability.Hum. 20: 141-154Crossref 251Blount Tsou W.L. Ristic Burr A.A. Ouyang Galante Scaglione K.M. Todi S.V. 2 prevents interacting Rad23.Nat. 5: 4638Crossref (41) Scholar); ER-associated (252Zhong Pittman R.N. Ataxin-3 binds VCP/p97 retrotranslocation ERAD substrates.Hum. 2006; 15: 2409-2420Crossref (153) transcription (253Evert B.O. Araujo Vieira-Saecker de Vos R.A. Harendza Klockgether Wullner represses chromatin binding, interaction histone deacetylase 3, deacetylation.J. Neurosci. 11474-11486Crossref (121) cytoskeletal (254Rodrigues do Carmo Costa T.L. Ferreira Bajanca Logarinho Maciel Absence leads disorganization increased death.Biochim. 1803: 1154-1163Crossref (31) (255Pfeiffer Luijsterburg M.S. Acs Wiegant W.W. Helfricht Herzog L.K. Minoia Bottcher Salomons F.A. van Attikum Dantuma N.P. consolidates MDC1-dependent double-strand break counteracting SUMO-targeted RNF4.EMBO 36: 1066-1083Crossref (36) Scholar)ATXN3LCysteine (256Ge Chen Qin Z. Liu Tan Zou Ren like (ATXN3L), member Josephin enzymes, promotes breast cancer proliferation Kruppel-like factor 5 (KLF5).Oncotarget. 21369-21378Crossref Scholar)BAP1Cysteine proteaseUCHK48DNA repair/transcription (257Yu Pak Hammond-Martel Ghram Rodrigue Daou Barbour Corbeil Hebert Drobetsky Masson J.Y. Di Noia Affar El Tumor suppressor repair.Proc. 111: 285-290Crossref (210) 258Okino Machida Frankland-Searby Y.J. BRCA1-associated (BAP1) antagonizes FoxK2 genes.J. 290: 1580-1591Abstract Scholar)BRCC36MetalloproteaseJAMM/MPN+K63DNA repair/cell cycle (259Wang Hurov Hofmann Elledge S.J. NBA1, new player Brca1 complex, resistance checkpoint control.Genes Dev. 23: 729-739Crossref (134) 260Yan Wang Hong Yang Lin He Q. Zheng Tang Yin Shao complex BRISC proper mitotic spindle assembly mammalian cells.J. 210: 209-224Crossref (29) Scholar)Cezanne∗Cysteine proteaseoutK11, K63NF-κB (261Hu Brittain G.C. Chang J.H. Puebla-Osorio Jin Zal Fu Y.X. Sun S.C. OTUD7B controls non-canonical deubiquitination TRAF3.Nature. 494: 371-374Crossref (133) Scholar)CSN5MetalloproteaseJAMM/MPN+K63DNA (262Pan Claret F.X. Jab1/CSN5 response, repair, cancer.Cancer Ther. 256-262Crossref (263Shackleford T.J. JAB1/CSN5: control cancer.Cell Div. 26Crossref (103) sorting (264Liu Shah Xiang Deng Z.B. Edmonds Jambor Kappes J.C. H.G. COP9-associated CSN5 exosomal sorting.Am. Pathol. 174: 1415-1425Abstract Scholar)CYLDCysteine proteaseoutK63, M1Cell (265Wickstrom S.A. Masoumi K.C. Khochbin Fassler Massoumi cell-cycle progression inactivating HDAC6 acetylated tubulin.EMBO 29: 131-144Crossref (104) NF-κB/WNT (266Komander tidies up dishevelled signaling.Mol. 37: 589-590Abstract 267Sun CYLD: tumor biological processes.Cell Death Differ. 25-34Crossref (268) Scholar)JOSD1Cysteine K63Endocytosis; (268Seki Gong Sakai JosD1, membrane-targeted enzyme, activated dynamics, motility, endocytosis.J. 288: 17145-17155Abstract Scholar)JOSD2Cysteine K63Metabolism (269Krassikova Nagarajan Queiroz A.L. Kacal Samakidis Vakifahmetoglu-Norberg Norberg JOSD2 positive regulator metabolism.Cell 28: 1091-1109Crossref (1) Scholar)MINDY1Cysteine proteaseMINDYK48Self-renewal stem cells (270James Zhao T.Y. Rahim Saxena Muthalif N.A. Uemura Tsuneyoshi Ong Igarashi Lim C.Y. Dunn N.R. Vardy L.A. MINDY1 polyamines embryonic self-renewal.Stem Cells. 1170-1178Crossref (8) Scholar)MINDY2Cysteine proteaseMINDYNon-specificMINDY3Cysteine proteaseMINDYK48MINDY4Cysteine proteaseMINDYK48MINDY4BCysteine proteaseMINDYK48MYSM1MetalloproteaseJAMM/MPN+K63Transcription (271Zhu Puc Ohgi K.A. Erdjument-Bromage Tempst Glass C.K. Rosenfeld M.G. H2A coordinating acetylation H1 dissociation transcriptional regulation.Mol. 27: 609-621Abstract immune (272Jiang X.X. Chou Jones Sanchez X.F. S.Y. Epigenetic antibody responses MYSM1.Sci. 13755Crossref Scholar)OTUB1∗Cysteine proteaseoutK48DNA (273Wu Gu OTUB1 stabilizes mismatch MSH2 blocking ubiquitination.J. 296: 100466Abstract (274Zhou Yu Manyam Schluns Otub1 CD8(+) T NK IL-15-mediated priming.Nat. 879-889Crossref Scholar)OTUB2Cysteine K63DNA (275Kato Nakajima Ui Muto-Terao Ogiwara Nakada Fine-tuning damage-dependent OTUB2 supports choice.Mol. 53: 617-630Abstract (56) (276Li X.Y. Mao X.Q. Han Q.Q. Jiang L.X. Qiu Y.M. Dai Gli2 stability OTUB2.Biochem. 505: 113-118Crossref (3) (124Garshott Sundaramoorthy Leonard Distinct ribosomal ubiquitylation events hierarchically organized.Elife. 9e54023Crossref (16) Scholar)OTUD1∗Cysteine proteaseoutK63Translation (277Lu Song Qi McNutt M.A. Mutations OTUD1 autoimmune disorders.J. Autoimmun. 94: 156-165Crossref Scholar)OTUD2∗Cysteine sorting; unfolded (278Ernst Mueller Ploegh Schlieker otubain YOD1 associates p97 facilitate dislocation ER.Mol. 28-38Abstract Scholar)OTUD3∗Cysteine proteaseoutK6, K48Translation (279Zhang Fang Ling Chu Zang et al.Acetylation-dependent OTUD3 MAVS innate antiviral immunity.Mol. 79: 304-319.e307Abstract Scholar)OTUD5∗Cysteine proteaseoutK48, K63Cell (280Cho Kim Park Kwon M.H. S.B. B.C. S.G. OTUD5 mTORC1 mTORC2 pathways.Cell 900-914Crossref (2) 281Park Choi H.K. Kwak Yoon mediates sequential PDCD5 p53 genotoxic stress.Cancer Lett. 357: 419-427Crossref (282Guo Kong Cai Ma Yi al.OTUD5 antitumor immunity stab

Язык: Английский

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In‐depth and 3‐dimensional exploration of the budding yeast phosphoproteome

EMBO Reports, Год журнала: 2021, Номер 22(2)

Опубликована: Янв. 25, 2021

Язык: Английский

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Proteome-scale movements and compartment connectivity during the eukaryotic cell cycle

Cell, Год журнала: 2024, Номер 187(6), С. 1490 - 1507.e21

Опубликована: Март 1, 2024

Cell cycle progression relies on coordinated changes in the composition and subcellular localization of proteome. By applying two distinct convolutional neural networks images millions live yeast cells, we resolved proteome-level dynamics both concentration during cell cycle, with resolution ∼20 classes. We show that a quarter proteome displays periodicity, proteins tending to be controlled either at level or concentration, but not both. Distinct levels protein regulation are preferentially utilized for different aspects being mostly involved control biophysical implementation program. present resource exploring global which will aid understanding fundamental biological process systems level.

Язык: Английский

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A metabolically controlled contact site between vacuoles and lipid droplets in yeast

Developmental Cell, Год журнала: 2024, Номер 59(6), С. 740 - 758.e10

Опубликована: Фев. 16, 2024

The lipid droplet (LD) organization proteins Ldo16 and Ldo45 affect multiple aspects of LD biology in yeast. They are linked to the biogenesis machinery seipin, their loss causes defects positioning, protein targeting, breakdown. However, molecular roles remained enigmatic. Here, we report that Ldo16/45 form a tether complex with Vac8 create vacuole (vCLIP) contact sites, which can absence seipin. phosphatidylinositol transfer (PITP) Pdr16 is further vCLIP-resident recruited specifically by Ldo45. While only an subpopulation engaged vCLIPs at glucose-replete conditions, nutrient deprivation results vCLIP expansion, impair lipophagy upon prolonged starvation. In summary, multifunctional control formation metabolically regulated site. Our studies suggest link between breakdown contribute deeper understanding how homeostasis maintained during metabolic challenges.

Язык: Английский

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Rad53 checkpoint kinase regulation of DNA replication fork rate via Mrc1 phosphorylation

eLife, Год журнала: 2021, Номер 10

Опубликована: Авг. 13, 2021

The Rad53 DNA checkpoint protein kinase plays multiple roles in the budding yeast cell response to replication stress. Key amongst these is its enigmatic role safeguarding forks. Using reactions reconstituted with purified proteins, we show phosphorylation of Sld3/7 or Dbf4-dependent blocks initiation whilst Mrc1 Mcm10 slows elongation. necessary and sufficient slow forks complete reactions; can also forks, but only absence unphosphorylated Mrc1. stimulates unwinding rate replicative helicase, CMG, prevents this. We that a phosphorylation-mimicking mutant cannot stimulate vitro partially rescues sensitivity rad53 null genotoxic stress vivo. Our results protects part by antagonising stimulation CMG unwinding.

Язык: Английский

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PCNA Loaders and Unloaders—One Ring That Rules Them All

Genes, Год журнала: 2021, Номер 12(11), С. 1812 - 1812

Опубликована: Ноя. 18, 2021

During each cell duplication, the entirety of genomic DNA in every must be accurately and quickly copied. Given short time available for chore, requirement many proteins, daunting amount present, replication poses a serious challenge to cell. A high level coordination between polymerases other chromatin-interacting proteins is vital complete this task. One most important maintaining such PCNA. PCNA multitasking protein that forms homotrimeric ring encircles DNA. It serves as processivity factor acts landing platform different interacting with chromatin. Therefore, signaling hub influences rate accuracy replication, regulates damage repair, controls chromatin formation during proper segregation sister chromatids. With so essential roles, recruitment turnover on utmost importance. Three different, conserved complexes are charge loading/unloading onto Replication C (RFC) canonical complex loading S-phase. The Ctf18 Elg1 (ATAD5 mammalian) form similar RFC, particular functions cell’s nucleus. Here we summarize our current knowledge about roles these factors yeast mammals.

Язык: Английский

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Systematic analysis of membrane contact sites in Saccharomyces cerevisiae uncovers modulators of cellular lipid distribution

eLife, Год журнала: 2022, Номер 11

Опубликована: Ноя. 10, 2022

Actively maintained close appositions between organelle membranes, also known as contact sites, enable the efficient transfer of biomolecules cellular compartments. Several such sites have been described well their tethering machineries. Despite these advances we are still far from a comprehensive understanding function and regulation most sites. To systematically characterize site proteomes, established high-throughput screening approach in Saccharomyces cerevisiae based on co-localization imaging. We imaged split fluorescence reporters for six different several which poorly characterized, background 1165 strains expressing mCherry-tagged yeast protein that has punctate distribution (a hallmark sites), under strong TEF2 promoter. By scoring both events effects reporter size abundance, discovered over 100 new potential residents effectors yeast. Focusing newly identified residents, three homologs Vps13 Atg2 multiple These proteins share lipid transport domain, thus expanding this family transporters. Analysis another candidate, Ypr097w, now call Lec1 (Lipid-droplet Ergosterol Cortex 1), revealed previously uncharacterized dynamically shifts droplets cell cortex, plays role ergosterol cell. Overall, our analysis expands universe creates rich database to mine functions, tethers, regulators.

Язык: Английский

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The regulatory landscape of the yeast phosphoproteome

Nature Structural & Molecular Biology, Год журнала: 2023, Номер 30(11), С. 1761 - 1773

Опубликована: Окт. 16, 2023

Язык: Английский

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Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Май 8, 2023

Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such domains, but mechanistic details of its regulation not well understood. Here, we show at atomic level how inositol pyrophosphates interact with domains subunits Vtc2 and Vtc3 to control activity VTC complex. inhibits catalytically active subunit Vtc4 homotypic SPX-SPX interactions via conserved helix α1 previously undescribed α7. Binding abrogates this interaction, thus activating Accordingly, activation is also achieved site-specific point mutations that disrupt interface. Structural data suggest ligand binding induces reorientation exposes modifiable α7, which might facilitate post-translational modification vivo. The variable composition these regions within domain family contribute diversified functions homeostasis.

Язык: Английский

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