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Missense Variants Reveal Functional Insights Into the Human ARID Family of Gene Regulators

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Deák, Gauri, Cook, Atlanta G.·2022·Journal of Molecular Biology
DOI 10.1016/j.jmb.2022.167529PMC PMC9077328

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Abstract

Missense variants are alterations to protein coding sequences that result in amino acid substitutions. They can be deleterious if the amino acid is required for maintaining structure or/and function, but are likely to be tolerated at other sites. Consequently, missense variation within a healthy population can mirror the effects of negative selection on protein structure and function, such that functional sites on proteins are often depleted of missense variants. Advances in high-throughput sequencing have dramatically increased the sample size of available human variation data, allowing for population-wide analysis of selective pressures. In this study, we developed a convenient set of tools, called 1D-to-3D, for visualizing the positions of missense variants on protein sequences and structures. We used these tools to characterize human homologues of the ARID family of gene regulators. ARID family members are implicated in multiple cancer types, developmental disorders, and immunological diseases but current understanding of their mechanistic roles is incomplete. Combined with phylogenetic and structural analyses, our approach allowed us to characterise sites important for protein-protein interactions, histone modification recognition, and DNA binding by the ARID proteins. We find that comparing missense depletion patterns among paralogs can reveal sub-functionalization at the level of domains. We propose that visualizing missense variants and their depletion on structures can serve as a valuable tool for complementing evolutionary and experimental findings.

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  • The overall missense depletion score for SALL4 protein (Vp) is 0.38.

    “we extracted population missense mutations and calculated an overall missense depletion score for SALL4 protein (Vp) of 0.38 (Deak & Cook, 2022) (Fig 1A).”

    From Structure of SALL4 zinc finger domain reveals link between AT-rich DNA binding and Okihiro syndrome (2023) · cites this paper as Deak & Cook, 2022

    The Results section (‘Genetic constraint in the ARID family’; page unavailable) defines Vp as the average density of missense variants for a protein, supporting the cited method. The paper does not report a Vp of 0.38 for SALL4; the citing sentence says its authors calculated that value themselves. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The N-terminal NuRD binding motif is comparatively depleted of population missense mutations (VdVp = 0.22).

    “Three regions were observed to be comparatively depleted of population missense mutations: the N-terminal NuRD binding motif (Lauberth & Rauchman, 2006) (VdVp = 0.22); a glutamine-rich (Q-rich) sequence that has been reported to participate in SALL protein homo- and heterodimer formation (VdVp = 0.50) (Sweetman et al, 2003); and ZFC4, which is essential for SALL4 function in mice (VdVp = 0.47) (P”

    From Structure of SALL4 zinc finger domain reveals link between AT-rich DNA binding and Okihiro syndrome (2023) · cites this paper as Deak & Cook, 2022

    The Introduction describes Vd/Vp as a measure of missense depletion, but the passages from Results concern ARID-family proteins, not the N-terminal NuRD-binding motif. Searches for the motif, SALL proteins, and 0.22 found no passage reporting the claimed depletion or value. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • The Q-rich sequence is comparatively depleted of population missense mutations (VdVp = 0.50).

    “Three regions were observed to be comparatively depleted of population missense mutations: the N-terminal NuRD binding motif (Lauberth & Rauchman, 2006) (VdVp = 0.22); a glutamine-rich (Q-rich) sequence that has been reported to participate in SALL protein homo- and heterodimer formation (VdVp = 0.50) (Sweetman et al, 2003); and ZFC4, which is essential for SALL4 function in mice (VdVp = 0.47) (P”

    From Structure of SALL4 zinc finger domain reveals link between AT-rich DNA binding and Okihiro syndrome (2023) · cites this paper as Deak & Cook, 2022

    The Results section on genetic constraint explains how Vd/Vp measures missense depletion in ARID-family proteins, but it does not report a Q-rich sequence with a Vd/Vp of 0.50. Searches of our copy for the Q-rich sequence, SALL proteins, and that value found no passage addressing the claimed region. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • ZFC4 is comparatively depleted of population missense mutations (VdVp = 0.47).

    “Three regions were observed to be comparatively depleted of population missense mutations: the N-terminal NuRD binding motif (Lauberth & Rauchman, 2006) (VdVp = 0.22); a glutamine-rich (Q-rich) sequence that has been reported to participate in SALL protein homo- and heterodimer formation (VdVp = 0.50) (Sweetman et al, 2003); and ZFC4, which is essential for SALL4 function in mice (VdVp = 0.47) (P”

    From Structure of SALL4 zinc finger domain reveals link between AT-rich DNA binding and Okihiro syndrome (2023) · cites this paper as Deak & Cook, 2022

    The Materials and Methods section explains how the paper calculates Vd/Vp ratios for ARID-family domains, but it does not report a result for ZFC4. Searches for ZFC4, SALL4, and a Vd/Vp value of 0.47 found no passage supporting the claimed depletion or number. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 71

  1. [1]Karczewski K.J. Francioli L.C. Tiao G. Cummings B.B. Alfoldi J. Wang Q. The mutational constraint spectrum quantified from variation in 141,456 humans Nature 581 2020 434 443 32461654 PMC7334197
  2. [2]Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. Analysis of protein-coding genetic variation in 60,706 humans Nature 536 2016 285 291 27535533 PMC5018207
  3. [4]Walsh R. Thomson K.L. Ware J.S. Funke B.H. Woodley J. McGuire K.J. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples Genet Med. 19 2017 192 203 27532257 PMC5116235
  4. [5]MacGowan A. Madeira F. Britto-Borges T. Schmittner M. Cole C. Barton G.J. Human Missense Variation is Constrained by Domain Structure and Highlights Functional and Pathogenic Residues bioRxiv 2017 127050
  5. [6]Havrilla J.M. Pedersen B.S. Layer R.M. Quinlan A.R. A map of constrained coding regions in the human genome Nature Genet. 51 2019 88 95 30531870 PMC6589356
  6. [8]Brenan L. Andreev A. Cohen O. Pantel S. Kamburov A. Cacchiarelli D. Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants Cell Rep. 17 2016 1171 1183 27760319 PMC5120861
  7. [9]Majithia A.R. Tsuda B. Agostini M. Gnanapradeepan K. Rice R. Peloso G. Prospective functional classification of all possible missense variants in PPARG Nature Genet. 48 2016 1570 1575 27749844 PMC5131844
  8. [10]Iqbal S. Perez-Palma E. Jespersen J.B. May P. Hoksza D. Heyne H.O. Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants Proc. Natl. Acad. Sci. USA 117 2020 28201 28211 33106425 PMC7668189
  9. [11]Bai D. Wang J. Li T. Chan R. Atalla M. Chen R.C. Differential Domain Distribution of gnomAD- and Disease-Linked Connexin Missense Variants Int. J. Mol. Sci. 22 2021 7832 34360596 PMC8346055
  10. [12]Hicks M. Bartha I. di Iulio J. Venter J.C. Telenti A. Functional characterization of 3D protein structures informed by human genetic diversity Proc. Natl. Acad. Sci. USA 116 2019 8960 8965 30988206 PMC6500140
  11. [13]Tang Z.Z. Sliwoski G.R. Chen G. Jin B. Bush W.S. Li B. PSCAN: Spatial scan tests guided by protein structures improve complex disease gene discovery and signal variant detection Genome Biol. 21 2020 217 32847609 PMC7448521
  12. [14]Sivley R.M. Dou X. Meiler J. Bush W.S. Capra J.A. Comprehensive Analysis of Constraint on the Spatial Distribution of Missense Variants in Human Protein Structures Am. J. Hum. Genet. 102 2018 415 426 29455857 PMC5985282
  13. [15]Iqbal S. Hoksza D. Perez-Palma E. May P. Jespersen J.B. Ahmed S.S. MISCAST: MIssense variant to protein StruCture Analysis web SuiTe Nucleic Acids Res. 48 2020 W132 W139 32402084 PMC7319582
  14. [16]Mittal P. Roberts C.W.M. The SWI/SNF complex in cancer - biology, biomarkers and therapy Nature Rev. Clin. Oncol. 17 2020 435 448 32303701 PMC8723792
  15. [17]Plch J. Hrabeta J. Eckschlager T. KDM5 demethylases and their role in cancer cell chemoresistance Int. J. Cancer 144 2019 221 231 30246379
  16. [18]Wu R.C. Young I.C. Chen Y.F. Chuang S.T. Toubaji A. Wu M.Y. Identification of the PTEN-ARID4B-PI3K pathway reveals the dependency on ARID4B by PTEN-deficient prostate cancer Nature Commun. 10 2019 4332 31551414 PMC6760172
  17. [19]Bogershausen N. Wollnik B. Mutational Landscapes and Phenotypic Spectrum of SWI/SNF-Related Intellectual Disability Disorders Front. Mol. Neurosci. 11 2018 252 30123105 PMC6085491
  18. [20]Wilsker D. Probst L. Wain H.M. Maltais L. Tucker P.W. Moran E. Nomenclature of the ARID family of DNA-binding proteins Genomics 86 2005 242 251 15922553
  19. [21]Blackledge N.P. Klose R.J. The molecular principles of gene regulation by Polycomb repressive complexes Nature Rev. Mol. Cell Biol. 22 2021 815 833 34400841 PMC7612013
  20. [22]Shandala T. Kortschak R.D. Saint R. The Drosophila retained/dead ringer gene and ARID gene family function during development Int. J. Dev. Biol. 46 2002 423 430 12141428
  21. [23]Baba A. Ohtake F. Okuno Y. Yokota K. Okada M. Imai Y. PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B Nature Cell Biol. 13 2011 668 675 21532585
  22. [24]Gong W. Zhou T. Mo J. Perrett S. Wang J. Feng Y. Structural insight into recognition of methylated histone tails by retinoblastoma-binding protein 1 J. Biol. Chem. 287 2012 8531 8540 22247551 PMC3318718
  23. [25]Lai A. Kennedy B.K. Barbie D.A. Bertos N.R. Yang X.J. Theberge M.C. RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest Mol. Cell Biol. 21 2001 2918 2932 11283269 PMC86920
  24. [26]Masuda K. Ripley B. Nishimura R. Mino T. Takeuchi O. Shioi G. Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo Proc. Natl. Acad. Sci. USA 110 2013 9409 9414 23676272 PMC3677444
  25. [27]Altenhoff A.M. Train C.M. Gilbert K.J. Mediratta I. Mendes de Farias T. Moi D. OMA orthology in 2021: website overhaul, conserved isoforms, ancestral gene order and more Nucleic Acids Res. 49 2021 D373-D9 PMC7779010 33174605
  26. [28]Katoh K. Standley D.M. MAFFT multiple sequence alignment software version 7: improvements in performance and usability Mol. Biol. Evol. 30 2013 772 780 23329690 PMC3603318
  27. [29]Needleman S.B. Wunsch C.D. A general method applicable to the search for similarities in the amino acid sequence of two proteins J. Mol. Biol. 48 1970 443 453 5420325
  28. [30]Waterhouse A.M. Procter J.B. Martin D.M. Clamp M. Barton G.J. Jalview Version 2–a multiple sequence alignment editor and analysis workbench Bioinformatics 25 2009 1189 1191 19151095 PMC2672624
  29. [31]Li H. Coghlan A. Ruan J. Coin L.J. Heriche J.K. Osmotherly L. TreeFam: a curated database of phylogenetic trees of animal gene families Nucleic Acids Res. 34 2006 D572 D580 16381935 PMC1347480
  30. [32]Holm L. DALI and the persistence of protein shape Protein Sci. 29 2020 128 140 31606894 PMC6933842
  31. [33]Blum M. Chang H.Y. Chuguransky S. Grego T. Kandasaamy S. Mitchell A. The InterPro protein families and domains database: 20 years on Nucleic Acids Res. 49 2021 D344 D354 33156333 PMC7778928
  32. [34]He S. Wu Z. Tian Y. Yu Z. Yu J. Wang X. Structure of nucleosome-bound human BAF complex Science 367 2020 875 881 32001526
  33. [35]Vinogradova M. Gehling V.S. Gustafson A. Arora S. Tindell C.A. Wilson C. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells Nature Chem. Biol. 12 2016 531 538 27214401
  34. [36]Johansson C. Velupillai S. Tumber A. Szykowska A. Hookway E.S. Nowak R.P. Structural analysis of human KDM5B guides histone demethylase inhibitor development Nature Chem. Biol. 12 2016 539 545 27214403
  35. [38]Jurrus E. Engel D. Star K. Monson K. Brandi J. Felberg L.E. Improvements to the APBS biomolecular solvation software suite Protein Sci. 27 2018 112 128 28836357 PMC5734301
  36. [39]Ashkenazy H. Abadi S. Martz E. Chay O. Mayrose I. Pupko T. ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules Nucleic Acids Res. 44 2016 W344 W350 27166375 PMC4987940
  37. [40]Zahn-Zabal M. Dessimoz C. Glover N.M. Identifying orthologs with OMA: A primer F1000Res. 9 2020 27 32089838 PMC7014581
  38. [41]Yang I.S. Son H. Kim S. Kim S. ISOexpresso: a web-based platform for isoform-level expression analysis in human cancer BMC Genom. 17 2016 631 PMC4983006 27519173
  39. [43]Firth H.V. Richards S.M. Bevan A.P. Clayton S. Corpas M. Rajan D. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources Am. J. Hum. Genet. 84 2009 524 533 19344873 PMC2667985
  40. [45]Turner T. Plot protein: visualization of mutations J. Clin. Bioinforma 3 2013 14 23876180 PMC3724591
  41. [46]Yates A.D. Achuthan P. Akanni W. Allen J. Allen J. Alvarez-Jarreta J. Ensembl 2020 Nucleic Acids Res. 48 2020 D682 D688 31691826 PMC7145704
  42. [47]Centore R.C. Sandoval G.J. Soares L.M.M. Kadoch C. Chan H.M. Mammalian SWI/SNF Chromatin Remodeling Complexes: Emerging Mechanisms and Therapeutic Strategies Trends Genet. 36 2020 936 950 32873422
  43. [48]Mashtalir N. D'Avino A.R. Michel B.C. Luo J. Pan J. Otto J.E. Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes Cell. 175 2018 1272–88 e20 PMC6791824 30343899
  44. [49]Mashtalir N. Suzuki H. Farrell D.P. Sankar A. Luo J. Filipovski M. A Structural Model of the Endogenous Human BAF Complex Informs Disease Mechanisms Cell. 183 2020 802-17 e24 PMC7717177 33053319
  45. [50]Longbotham J.E. Chio C.M. Dharmarajan V. Trnka M.J. Torres I.O. Goswami D. Histone H3 binding to the PHD1 domain of histone demethylase KDM5A enables active site remodeling Nature Commun. 10 2019 94 30626866 PMC6327041
  46. [51]Torres I.O. Kuchenbecker K.M. Nnadi C.I. Fletterick R.J. Kelly M.J. Fujimori D.G. Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism Nature Commun. 6 2015 6204 25686748 PMC5080983
  47. [52]Zhang Y. Yang H. Guo X. Rong N. Song Y. Xu Y. The PHD1 finger of KDM5B recognizes unmodified H3K4 during the demethylation of histone H3K4me2/3 by KDM5B Protein Cell. 5 2014 837 850 24952722 PMC4225485
  48. [53]Wang G.G. Song J. Wang Z. Dormann H.L. Casadio F. Li H. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger Nature 459 2009 847 851 19430464 PMC2697266
  49. [54]Klein B.J. Piao L. Xi Y. Rincon-Arano H. Rothbart S.B. Peng D. The histone-H3K4-specific demethylase KDM5B binds to its substrate and product through distinct PHD fingers Cell Rep. 6 2014 325 335 24412361 PMC3918441
  50. [55]Longbotham J.E. Kelly M.J.S. Fujimori D.G. Recognition of Histone H3 Methylation States by the PHD1 Domain of Histone Demethylase KDM5A ACS Chem. Biol. 2021 PMC8380758 33621062
  51. [57]Wu R.C. Jiang M. Beaudet A.L. Wu M.Y. ARID4A and ARID4B regulate male fertility, a functional link to the AR and RB pathways Proc. Natl. Acad. Sci. USA 110 2013 4616 4621 23487765 PMC3606970
  52. [58]Lei M. Feng Y. Zhou M. Yang Y. Loppnau P. Li Y. Crystal structure of chromo barrel domain of RBBP1 Biochem. Biophys. Res. Commun. 496 2018 1344 1348 29408527
  53. [59]Fleischer T.C. Yun U.J. Ayer D.E. Identification and characterization of three new components of the mSin3A corepressor complex Mol. Cell Biol. 23 2003 3456 3467 12724404 PMC164750
  54. [60]Wu M.Y. Tsai T.F. Beaudet A.L. Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain Genes Dev. 20 2006 2859 2870 17043311 PMC1619944
  55. [61]Gong W. Wang J. Perrett S. Feng Y. Retinoblastoma-binding protein 1 has an interdigitated double Tudor domain with DNA binding activity J. Biol. Chem. 289 2014 4882 4895 24379399 PMC3931050
  56. [62]Ren J. Yao H. Hu W. Perrett S. Gong W. Feng Y. Structural basis for the DNA-binding activity of human ARID4B Tudor domain J. Biol. Chem. 2021 100506 33675746 PMC8038949
  57. [63]Iwahara J. Iwahara M. Daughdrill G.W. Ford J. Clubb R.T. The structure of the Dead ringer-DNA complex reveals how AT-rich interaction domains (ARIDs) recognize DNA EMBO J. 21 2002 1197 1209 11867548 PMC125891
  58. [64]Kim S. Zhang Z. Upchurch S. Isern N. Chen Y. Structure and DNA-binding sites of the SWI1 AT-rich interaction domain (ARID) suggest determinants for sequence-specific DNA recognition J. Biol. Chem. 279 2004 16670 16676 14722072
  59. [65]Cai S. Zhu L. Zhang Z. Chen Y. Determination of the three-dimensional structure of the Mrf2-DNA complex using paramagnetic spin labeling Biochemistry 46 2007 4943 4950 17407261 PMC2527749
  60. [66]Tu S. Teng Y.C. Yuan C. Wu Y.T. Chan M.Y. Cheng A.N. The ARID domain of the H3K4 demethylase RBP2 binds to a DNA CCGCCC motif Nature Struct. Mol. Biol. 15 2008 419 421 18270511
  61. [67]Liu G. Huang Y.J. Xiao R. Wang D. Acton T.B. Montelione G.T. Solution NMR structure of the ARID domain of human AT-rich interactive domain-containing protein 3A: a human cancer protein interaction network target Proteins 78 2010 2170 2175 20455271 PMC2869213
  62. [68]Hata K. Takashima R. Amano K. Ono K. Nakanishi M. Yoshida M. Arid5b facilitates chondrogenesis by recruiting the histone demethylase Phf2 to Sox9-regulated genes Nature Commun. 4 2013 2850 24276541
  63. [69]Yamakawa T. Whitson R.H. Li S.L. Itakura K. Modulator recognition factor-2 is required for adipogenesis in mouse embryo fibroblasts and 3T3-L1 cells Mol. Endocrinol. 22 2008 441 453 17962384 PMC5419636
  64. [70]Garton J. Barron M.D. Ratliff M.L. Webb C.F. New Frontiers: ARID3a in SLE Cells 8 2019 PMC6830313 31554207
  65. [71]Le Bouffant R. Cunin A.C. Buisson I. Cartry J. Riou J.F. Umbhauer M. Differential expression of arid5b isoforms in Xenopus laevis pronephros Int. J. Dev. Biol. 58 2014 363 368 25354457
  66. [72]Yang N. Xu R.M. Structure and function of the BAH domain in chromatin biology Crit. Rev. Biochem. Mol. Biol. 48 2013 211 221 23181513
  67. [73]Fan H. Lu J. Guo Y. Li D. Zhang Z.M. Tsai Y.H. BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis Nature Genet. 52 2020 1384 1396 33139953 PMC8330957
  68. [74]Kuo A.J. Song J. Cheung P. Ishibe-Murakami S. Yamazoe S. Chen J.K. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome Nature 484 2012 115 119 22398447 PMC3321094
  69. [75]Ren W. Fan H. Grimm S.A. Kim J.J. Li L. Guo Y. DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation Nature Commun. 12 2021 2490 33941775 PMC8093215
  70. [77]Tillotson R. Selfridge J. Koerner M.V. Gadalla K.K.E. Guy J. De Sousa D. Radically truncated MeCP2 rescues Rett syndrome-like neurological defects Nature 550 2017 398 401 29019980 PMC5884422
  71. [78]Mugal C.F. Ellegren H. Substitution rate variation at human CpG sites correlates with non-CpG divergence, methylation level and GC content Genome Biol. 12 2011 R58 21696599 PMC3218846

Cited by

Sorted by citations

Authors
Deák, G., & Cook, A. G.
Affiliations
Wellcome Centre for Cell Biology (GB)
Corresponding author
Cook, Atlanta G.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2022-05
Volume
434
Issue
9
Pages
167529
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2022.167529
PMC
PMC9077328
OpenAlex
W4225301591
Cited by
20
References
10
Citations by year
2026: 7 · 2025: 4 · 2024: 6 · 2023: 3
FWCI
1.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
Wellcome Trust (200898, 200898/Z/16/Z, 203149)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords
missense mutations, regulatory genes, protein evolution, negative selection, protein-protein interaction, DNA binding, subfunctionalization, paralogs, protein structure, human genetic variation
MeSH terms
Amino Acid Sequence, DNA-Binding Proteins, Genes, Regulator, Humans, Phylogeny, Amino Acid Substitution, Mutation, Missense

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