Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo

Autoři: Jessica K. Sawyer aff001;  Zahra Kabiri aff001;  Ruth A. Montague aff001;  Scott R. Allen aff002;  Rebeccah Stewart aff001;  Sarah V. Paramore aff001;  Erez Cohen aff002;  Hamed Zaribafzadeh aff001;  Christopher M. Counter aff001;  Donald T. Fox aff001
Působiště autorů: Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, North Carolina, United States of America aff001;  Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, United States of America aff002;  Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina, United States of America aff003
Vyšlo v časopise: Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo. PLoS Genet 16(12): e1009228. doi:10.1371/journal.pgen.1009228
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009228


Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and regulation. Here, by altering codon usage as a novel platform to control signaling output, we screened the Drosophila genome for modifiers specific to either weak or strong Ras-driven eye phenotypes. Our screen enriched for regions of the genome not previously connected with Ras phenotypic modification. We mapped the underlying gene from one modifier to the ribosomal gene RpS21. In multiple contexts, we show that RpS21 preferentially influences weak Ras/MAPK signaling outputs. These data show that codon usage manipulation can identify new, output-specific signaling regulators, and identify RpS21 as an in vivo Ras/MAPK phenotypic regulator.

Klíčová slova:

Drosophila melanogaster – ERK signaling cascade – Eyes – Genomic signal processing – MAPK signaling cascades – Ras signaling – Regulator genes – Signal processing


1. Hayashi S, Ogura Y. ERK signaling dynamics in the morphogenesis and homeostasis of Drosophila. Curr Opin Genet Dev. 2020;63:9–15. doi: 10.1016/j.gde.2020.01.004 32145545

2. Karim FD, Chang HC, Therrien M, Wassarman DA, Laverty T, Rubin GM. A screen for genes that function downstream of Ras1 during Drosophila eye development. Genetics. 1996;143:315–29. 8722784

3. Maixner A, Hecker TP, Phan QN, Wassarman DA. A screen for mutations that prevent lethality caused by expression of activated sevenless and ras1 in the Drosophila embryo. Dev Genet. 1998;23:347–61. doi: 10.1002/(SICI)1520-6408(1998)23:4<347::AID-DVG9>3.0.CO;2-C 9883586

4. Therrien M, Morrison DK, Wong AM, Rubin GM. A genetic screen for modifiers of a kinase suppressor of Ras-dependent rough eye phenotype in Drosophila. Genetics. 2000;156:1231–42. 11063697

5. Chang HC, Rubin GM. 14-3-3ε positively regulates Ras-mediated signaling in Drosophila. Genes Dev. 1997;11:1132–9. doi: 10.1101/gad.11.9.1132 9159394

6. Rebay I, Chen F, Hsiao F, Kolodziej PA, Kuang BH, Laverty T, et al. A genetic screen for novel components of the Ras/mitogen-activated protein kinase signaling pathway that interact with the yan gene of Drosophila identifies split ends, a new RNA recognition motif-containing protein. Genetics. 2000;154:695–712. 10655223

7. Dickson BJ, van der Straten A. Dom\’\inguez M. & Hafen E. Mutations Modulating Raf signaling in Drosophila eye development. Genetics. 1996;142:163–71. 8770593

8. Gaul U., Chang H., Choi T., Karim F. & Rubin G. M. Identification of ras targets using a genetic approach. Ciba Found. Symp. 176, 85–92– discussion 92–5 (1993). doi: 10.1002/9780470514450.ch6 8299428

9. Therrien M, Chang HC, Solomon NM, Karim FD, Wassarman DA, Rubin GM. KSR, a novel protein kinase required for RAS signal transduction. Cell. 1995;83:879–88. doi: 10.1016/0092-8674(95)90204-x 8521512

10. Kornfeld K. Hom D. B. & Horvitz H. R. The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell. 1995;83:903–13. doi: 10.1016/0092-8674(95)90206-6 8521514

11. Sundaram M, Han M, The C. elegans ksr-1 gene encodes a novel raf-related kinase involved in Ras-mediated signal transduction. Cell. 1995;83:889–901. doi: 10.1016/0092-8674(95)90205-8 8521513

12. Singh N. & Han M. sur-2, a novel gene, functions late in the let-60 ras-mediated signaling pathway during Caenorhabditis elegans vulval induction. Genes Dev. 9, 2251–2265 (1995). doi: 10.1101/gad.9.18.2251 7557379

13. Battu G. Hoier, E. F. & Hajnal, A. The C. elegans G-protein-coupled receptor SRA-13 inhibits RAS/MAPK signalling during olfaction and vulval development. Development. 2003;130:2567–77. doi: 10.1242/dev.00497 12736202

14. Berset T., Hoier E. F., Battu G., Canevascini S. & Hajnal A. Notch inhibition of RAS signaling through MAP kinase phosphatase LIP-1 during C. elegans vulval development. Science (80-.). 291, 1055–1058 (2001). doi: 10.1126/science.1055642 11161219

15. Friedman A, Perrimon N. A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling. Nature. 2006;444:230–4. doi: 10.1038/nature05280 17086199

16. Ashton-Beaucage D, Udell CM, Gendron P, Sahmi M, Lefrancois M, Baril C, et al. A Functional Screen Reveals an Extensive Layer of Transcriptional and Splicing Control Underlying RAS/MAPK Signaling in Drosophila. PLoS Biol. 2014;12. doi: 10.1371/journal.pbio.1001809 24643257

17. Friedman A. A., Tucker G., Singh R., Yan D., Vinayagam A., Hu Y., et al. Proteomic and functional genomic landscape of receptor tyrosine kinase and ras to extracellular signal-regulated kinase signaling. Sci. Signal. 4, rs10 (2011). doi: 10.1126/scisignal.2002029 22028469

18. Toettcher JE, Weiner OD, Lim WA. Using optogenetics to interrogate the dynamic control of signal transmission by the Ras/Erk module. Cell. 2013;155:1422–34. doi: 10.1016/j.cell.2013.11.004 24315106

19. Wilson M. Z., Ravindran P. T., Lim W. A. & Toettcher J. E. Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control. Mol. Cell 67, 757–769.e5 (2017). doi: 10.1016/j.molcel.2017.07.016 28826673

20. Johnson HE, Goyal Y, Pannucci NL, Shupbach T, Shvartsman SY, Toettcher JE. The Spatiotemporal Limits of Developmental Erk Signaling. Dev Cell. 2017;40:185–92. doi: 10.1016/j.devcel.2016.12.002 28118601

21. Goyal Y, Jindal GA, Pelliccia JL, Yamaya K, Yeung E, Futran AS, et al. Divergent effects of intrinsically active MEK variants on developmental Ras signaling. Nat Genet. 2017;49:465–9. doi: 10.1038/ng.3780 28166211

22. Pershing NLK, Lampson BL, Belsky JA, Kaltenbrun E, MacAlpine DM, Counter CM. Rare codons capacitate Kras-driven de novo tumorigenesis. J Clin Invest. 2015;125:222–33. doi: 10.1172/JCI77627 25437878

23. Ali M, Kaltenbrun E, Anderson GR, Stephens SJ, Arena S, Bardelli A, et al. Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. Nat Commun. 2017;8:15617. doi: 10.1038/ncomms15617 28593995

24. Neuman-Silberberg FS, Schejter E, Hoffmann FM, Shilo BZ. The Drosophila ras oncogenes: structure and nucleotide sequence. Cell. 1984;37:1027–33. doi: 10.1016/0092-8674(84)90437-9 6430564

25. Quax TEF, Claassens NJ, Söll D, van der Oost J. Codon Bias as a Means to Fine-Tune Gene Expression. Mol Cell. 2015;59:149–61. doi: 10.1016/j.molcel.2015.05.035 26186290

26. Wang Y, Li C, Khan MRI, Wang Y, Ruan Y, Zhao B, et al. An Engineered Rare Codon Device for Optimization of Metabolic Pathways. Sci Rep. 2016;6. doi: 10.1038/s41598-016-0015-2 28442741

27. Lampson BL, Pershing NLK, Prinz JA, Lacsina JR, Marzluff WF, Nicchitta CV, et al. Rare Codons Regulate KRas Oncogenesis. Curr Biol. 2013;23:70–5. doi: 10.1016/j.cub.2012.11.031 23246410

28. Li S, Balmain A, Counter CM. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer. 2018;18:767–77. doi: 10.1038/s41568-018-0076-6 30420765

29. Ikemura T. Codon usage and tRNA content in unicellular and multicellular organisms. Mol Biol Evol. 1985;2:13–34. doi: 10.1093/oxfordjournals.molbev.a040335 3916708

30. Sablok G, Nayak KC, Vazquez F, Tatarinova TV. Synonymous codon usage, GC 3, and evolutionary patterns across plastomes of three pooid model species: Emerging grass genome models for monocots. Mol Biotechnol. 2011;49:116–28. doi: 10.1007/s12033-011-9383-9 21308422

31. Moriyama EN, Powell JR. Codon usage bias and tRNA abundance in Drosophila. J Mol Evol. 1997;45:514–23. doi: 10.1007/pl00006256 9342399

32. Urrutia AO, Hurst LD. Codon usage bias covaries with expression breadth and the rate of synonymous evolution in humans, but this is not evidence for selection. Genetics. 2001.

33. Yang Z, Nielsen R. Mutation-selection models of codon substitution and their use to estimate selective strengths on codon usage. Mol Biol Evol. 2008;25:568–79. doi: 10.1093/molbev/msm284 18178545

34. Hense W, Anderson N, Hutter S. Stephan., W., Parsch, J., Carlini, D.B. Experimentally increased codon bias in the Drosophila Adh gene leads to an increase in larval, but not adult, alcohol dehydrogenase activity. Genetics. 2010;184:547–55. doi: 10.1534/genetics.109.111294 19966063

35. Burow DA, Martin S, Quail JF, Alhusaini N, Coller J, Cleary MD. Attenuated Codon Optimality Contributes to Neural-Specific mRNA Decay in Drosophila. Cell Rep. 2018;24:1704–12. doi: 10.1016/j.celrep.2018.07.039 30110627

36. Plotkin JB, Kudla G. Synonymous but not the same: the causes and consequences of codon bias. Nat Rev Genet. 2011;12:32–42. doi: 10.1038/nrg2899 21102527

37. Hanson G, Coller J. Translation and Protein Quality Control: Codon optimality, bias and usage in translation and mRNA decay. Nat Rev Mol Cell Biol. 2018;19:20–30. doi: 10.1038/nrm.2017.91 29018283

38. Sharp PM, Li WH. The codon adaptation index-a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res. 1987;15:1281–95. doi: 10.1093/nar/15.3.1281 3547335

39. Fortini ME, Simon MA, Rubin GM. Signalling by the sevenless protein tyrosine kinase is mimicked by Ras1 activation. Nature. 1992;355:559–61. doi: 10.1038/355559a0 1311054

40. Gaul U, Mardon G, Rubin GM. A putative Ras GTPase activating protein acts as a negative regulator of signaling by the Sevenless receptor tyrosine kinase. Cell. 1992;68:1007–19. doi: 10.1016/0092-8674(92)90073-l 1547500

41. Biggs WH, Zavitz KH, Dickson B, van der Straten A, Brunner D, Hafen E, et al. The Drosophila rolled locus encodes a MAP kinase required in the sevenless signal transduction pathway. EMBO J. 1994;13:1628–35. 8157002

42. De Rooij J, Bos JL. Minimal Ras-binding domain of Raf1 can be used as an activation-specific probe for Ras. Oncogene. 1997;14:623–5. doi: 10.1038/sj.onc.1201005 9053862

43. Ikemura T. Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes: A proposal for a synonymous codon choice that is optimal for the E coli translational system J Mol Biol. 1981;151:389–409. doi: 10.1016/0022-2836(81)90003-6 6175758

44. Spanjaard RA, Van Duin J. Translation of the sequence AGG-AGG yields 50% ribosomal frameshift. Proc Natl Acad Sci U S A. 1988;85:7967–71. doi: 10.1073/pnas.85.21.7967 3186700

45. Kramer E. B. & Farabaugh, P. J. The frequency of translational misreading errors in E. coli is largely determined by tRNA competition. RNA. 2007;13:87–96. doi: 10.1261/rna.294907 17095544

46. Rosenberg AH, Goldman E, Dunn JJ, Studier FW, Zubay G. Effects of consecutive AGG codons on translation in Escherichia coli, demonstrated with a versatile codon test system. J Bacteriol. 1993;175:716–22. doi: 10.1128/jb.175.3.716-722.1993 7678594

47. Chu D, Kazana E, Bellanger N, Singh T, Tuite MF, von der Haar T. Translation elongation can control translation initiation on eukaryotic mRNAs. EMBO J. 2014;33:21–34. doi: 10.1002/embj.201385651 24357599

48. Fu J, Dang Y, Counter C, Liu Y. Codon usage regulates human KRAS expression at both transcriptional and translational levels. J Biol Chem. 2018;293:17929–40. doi: 10.1074/jbc.RA118.004908 30275015

49. Zhoua Z, Dang Y, Zhou M, Li L, Yu CH, Fu J, et al. Codon usage is an important determinant of gene expression levels largely through its effects on transcription. Proc Natl Acad Sci U S A. 2016;113:E6117–25. doi: 10.1073/pnas.1606724113 27671647

50. Harigaya Y, Parker R. Analysis of the association between codon optimality and mRNA stability in Schizosaccharomyces pombe. BMC Genomics. 2016;17. doi: 10.1186/s12864-015-2333-3 26725242

51. Bazzini AA, Del Viso F, Moreno-Mateos MA, Johnstone TG, Vejnar CE, Qin Y, et al. Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition. EMBO J. 2016;35:2087–103. doi: 10.15252/embj.201694699 27436874

52. Mishima Y, Tomari Y. Codon Usage and 3’ UTR Length Determine Maternal mRNA Stability in Zebrafish. Mol Cell. 2016;61:874–85. doi: 10.1016/j.molcel.2016.02.027 26990990

53. Radhakrishnan A., Chen Y.H., Martin S., Alhusaini N., Green R., Coller J. The DEAD-Box Protein Dhh1p Couples mRNA Decay and Translation by Monitoring Codon Optimality. Cell 167, 122–132.e9 (2016). doi: 10.1016/j.cell.2016.08.053 27641505

54. Struhl G, Basler K. Organizing activity of wingless protein in Drosophila. Cell. 1993;72:527–40. doi: 10.1016/0092-8674(93)90072-x 8440019

55. Karim FD, Rubin GM. Ectopic expression of activated Ras1 induces hyperplastic growth and increased cell death in Drosophila imaginal tissues. Development. 1998;125:1–9. 9389658

56. Jiang Y, Scott KL, Kwak SJ, Chen R, Mardon G. Sds22/PP1 links epithelial integrity and tumor suppression via regulation of myosin II and JNK signaling. Oncogene. 2011;30:3248–60. doi: 10.1038/onc.2011.46 21399659

57. Shen J, Curtis C, Tavaré S, Tower J. A screen of apoptosis and senescence regulatory genes for life span effects when over-expressed in Drosophila. Aging (Albany NY). 2009;1 (191–211). doi: 10.18632/aging.100018 20157509

58. Cox AD, Der CJ. The dark side of Ras: Regulation of apoptosis. Oncogene. 2003;22:8999–9006. doi: 10.1038/sj.onc.1207111 14663478

59. Karnoub AE, Weinberg RA. Ras oncogenes: Split personalities. Nat Rev Mol Cell Biol. 2008;9:517–31. doi: 10.1038/nrm2438 18568040

60. Rebay I, Rubin GM. Yan functions as a general inhibitor of differentiation and is negatively regulated by activation of the Ras1/MAPK pathway. Cell. 1995;81:857–66. doi: 10.1016/0092-8674(95)90006-3 7781063

61. Lai ZC, Rubin GM. Negative control of photoreceptor development in Drosophila by the product of the yan gene, an ETS domain protein. Cell. 1992;70:609–20. doi: 10.1016/0092-8674(92)90430-k 1505027

62. Ray M, Lakhotia SC. The commonly used eye-specific sev-GAL4 and GMR-GAL4 drivers in Drosophila melanogaster are expressed in tissues other than eyes also. J Genet. 2015;94:407–16. doi: 10.1007/s12041-015-0535-8 26440079

63. Rørth P. A modular misexpression screen in Drosophila detecting tissue-specific phenotypes. Proc Natl Acad Sci U S A. 1996;93:12418–22. doi: 10.1073/pnas.93.22.12418 8901596

64. Cook RK, Christensen SJ, Deal JA, Coburn RA, Deal ME, Gresens JM, et al. The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome. Genome Biol. 2012;13:R21. doi: 10.1186/gb-2012-13-3-r21 22445104

65. Török I, Hermann-Horle D, Kiss I, Tick G, Speer G, Schmitt R, et al. Down-regulation of RpS21, a putative translation initiation factor interacting with P40, produces viable minute imagos and larval lethality with overgrown hematopoietic organs and imaginal discs. Mol Cell Biol. 1999;19:2308–21. doi: 10.1128/mcb.19.3.2308 10022917

66. Nilson LA, Schüpbach T, Schüpbach T. 7 EGF Receptor Signaling in Drosophila Oogenesis. Curr Top Dev Biol. 1998;44:203–43.

67. Cheung LS, Schüpbach T, Shvartsman SY. Pattern formation by receptor tyrosine kinases: Analysis of the Gurken gradient in Drosophila oogenesis. Curr Opin Genet Dev. 2011;21:719–25. doi: 10.1016/j.gde.2011.07.009 21862318

68. Halfar K, Rommel C, Stocker H, Hafen E. Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity. Development. 2001;128:1687–96. 11290305

69. Sears R, Nuckolis F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 2000;14:2501–14. doi: 10.1101/gad.836800 11018017

70. Magudia K, Lahoz A, Hall A. K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc. J Cell Biol. 2012;198:185–94. doi: 10.1083/jcb.201202108 22826122

71. Tsai W. B., Aiba I., Long Y., Lin H.K., Feun L., Savaraj, et al. Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells. Cancer Res. 72, 2622–2633 (2012). doi: 10.1158/0008-5472.CAN-11-3605 22461507

72. Prober DA, Edgar BA. Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing. Genes Dev. 2002;16:2286–99. doi: 10.1101/gad.991102 12208851

73. Rauen K, The A. RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355–69. doi: 10.1146/annurev-genom-091212-153523 23875798

74. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72:2457–67. doi: 10.1158/0008-5472.CAN-11-2612 22589270

75. Bridges C. B. & Morgan T. H. The third-chromosome group of mutant characters of Drosophila melanogaster,. The third-chromosome group of mutant characters of Drosophila melanogaster, (Carnegie Institution of Washington, 2011). doi: 10.5962/bhl.title.24013

76. Schultz J. The Minute Reaction in the Development of DROSOPHILA MELANOGASTER. Genetics. 1929;14:366–419. 17246581

77. Marygold SJ, Roote J, Reuter G, Lambertsson A, Ashburner M, Millburn GH, et al. The ribosomal protein genes and Minute loci of Drosophila melanogaster. Genome Biol. 2007;8. doi: 10.1186/gb-2007-8-10-r216 17927810

78. Duttagupta A. K. & Shellenbarger D. L. Genetics of Minute Locus in Drosophila Melanogaster. in Development and Neurobiology of Drosophila 25–33 (Springer US, 1980). doi: 10.1007/978-1-4684-7968-3_3 6779793

79. Watson KL, Johnson TK, Denell RE. Lethal(1)aberrant immune response mutations leading to melanotic tumor formation in Drosophila melanogaster. Dev Genet. 1991;12:173–87. doi: 10.1002/dvg.1020120302 1907895

80. Watson KL, Konrad KD, Woods DF, Bryant PJ. Drosophila homolog of the human S6 ribosomal protein is required for tumor suppression in the hematopoietic system. Proc Natl Acad Sci U S A. 1992;89:11302–6. doi: 10.1073/pnas.89.23.11302 1454811

81. Stewart MJ, Denell R. Mutations in the Drosophila gene encoding ribosomal protein S6 cause tissue overgrowth. Mol Cell Biol. 1993;13:2524–35. doi: 10.1128/mcb.13.4.2524 8384310

82. Marygold SJ, Coelho CMA, Leevers SJ. Genetic analysis of RpL38 and RpL5, two minute genes located in the centric heterochromatin of chromosome 2 of Drosophila melanogaster. Genetics. 2005;169:683–95. doi: 10.1534/genetics.104.034124 15520262

83. Lin JI, Mitchell NC, Kalcina M, Tchobubrieva E, Stewart MJ, Marygold SJ, et al. Drosophila ribosomal protein mutants control tissue growth non-autonomously via effects on the prothoracic gland and ecdysone. PLoS Genet. 2011;7. doi: 10.1371/journal.pgen.1002408 22194697

84. Amsterdam A, Sadler KC, Lai K, Farrington S, Bronson RT, Lees JA, et al. Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol. 2004;2. doi: 10.1371/journal.pbio.0020139 15138505

85. Ajore R, Raiser D, McConkey M, Joud M, Boidol B, Mar B, et al. Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP 53 mutations. EMBO Mol Med. 2017;9:498–507. doi: 10.15252/emmm.201606660 28264936

86. Russo A. & Russo G. Ribosomal proteins control or bypass p53 during nucleolar stress. International Journal of Molecular Sciences vol. 18 (2017). doi: 10.3390/ijms18010140 28085118

87. Chen J, Guo K, Kastan MB. Interactions of nucleolin and ribosomal protein L26 (RPL26) in translational control of human p53 mRNA. J Biol Chem. 2012;287:16467–76. doi: 10.1074/jbc.M112.349274 22433872

88. Sloan KE, Bohnsack MT, Watkins NJ. The 5S RNP Couples p53 Homeostasis to Ribosome Biogenesis and Nucleolar Stress. Cell Rep. 2013;5:237–47. doi: 10.1016/j.celrep.2013.08.049 24120868

89. Donati G, Peddigari S, Mercer CA, Thomas G. 5S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 Checkpoint. Cell Rep. 2013;4:87–98. doi: 10.1016/j.celrep.2013.05.045 23831031

90. Wan F, Anderson DE, Barnitz RA, Snow A, Bidere N, Zheng L, et al. Ribosomal Protein S3: A KH Domain Subunit in NF-κB Complexes that Mediates Selective Gene Regulation. Cell. 2007;131:927–39. doi: 10.1016/j.cell.2007.10.009 18045535

91. Donati G, Brighenti E, Vici M, Mazzini G, Trere D, Montanaro L, et al. Selective inhibition of rrna transcription downregulates E2F-1: A new p53-independent mechanism linking cell growth to cell proliferation. J Cell Sci. 2011;124:3017–28. doi: 10.1242/jcs.086074 21878508

92. Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E, et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature. 2008;456:971–5. doi: 10.1038/nature07449 19011615

93. Lessard F, Igelmann S, Trahan C, Huot G, Saint-Germain E, Mignacca L, et al. Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway. Nat Cell Biol. 2018;20:789–99. doi: 10.1038/s41556-018-0127-y 29941930

94. Wan Y, Zhang Q, Zhang Z, Song B, Wang X, Zhang Y, et al. Transcriptome analysis reveals a ribosome constituents disorder involved in the RPL5 downregulated zebrafish model of Diamond-Blackfan anemia. BMC Med Genet. 2016;9. doi: 10.1186/s12881-016-0273-7 26843370

95. Mirabello L, Khincha PP, Ellis SR, Giri N, Brodie S, Chanrasekharappa SC, et al. Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation. J Med Genet. 2017;54:417–25. doi: 10.1136/jmedgenet-2016-104346 28280134

96. Horos R, Ijspeert H, Popisilova D, Sendtner R, Andrieu-Soler C, Taskesen E, et al. Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts. Blood. 2012;119:262–72. doi: 10.1182/blood-2011-06-358200 22058113

97. Farrar JE, Vlachos A, Atsidaftos E, Carlson-Donohoe H, Markello TC, Arceci RJ, et al. Ribosomal protein gene deletions in Diamond-Blackfan anemia. Blood. 2011;118:6943–51. doi: 10.1182/blood-2011-08-375170 22045982

98. Shi Z., Fujii K., Kovary K.M., Genuth N.R., Rost H.L., Teruel M.N., et al. Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide. Mol. Cell 67, 71–83.e7 (2017). doi: 10.1016/j.molcel.2017.05.021 28625553

99. Lessard F., Brakier-Gingras L. & Ferbeyre G. Ribosomal Proteins Control Tumor Suppressor Pathways in Response to Nucleolar Stress. BioEssays vol. 41 (2019). doi: 10.1002/bies.201800183 30706966

100. Warner JR, McIntosh KB. How Common Are Extraribosomal Functions of Ribosomal Proteins? Mol Cell. 2009;34:3–11. doi: 10.1016/j.molcel.2009.03.006 19362532

101. Dionne KL, Bergeron D, Landry-Voyer AM, Bachand F. The 40S ribosomal protein uS5 (RPS2) assembles into an extraribosomal complex with human ZNF277 that competes with the PRMT3– uS5 interaction. J Biol Chem. 2019;294:1944–55. doi: 10.1074/jbc.RA118.004928 30530495

102. Simsek D., Tiu G.C., Flynn R.A., Byeon G.W., Leppek K., Xu A.F., et al. The Mammalian Ribo-interactome Reveals Ribosome Functional Diversity and Heterogeneity. Cell 169, 1051–1065.e18 (2017). doi: 10.1016/j.cell.2017.05.022 28575669

103. Xue S, Tian S, Fujii K, Kladwang W, Das R, Barna M. RNA regulons in Hox 5[prime] UTRs confer ribosome specificity to gene regulation. Nature. 2015;517:33–8. doi: 10.1038/nature14010 25409156

104. Wang T, Wang ZY, Zeng LY, Gao YZ, Yan YX, Zhang Q. Down-regulation of ribosomal protein RPS21 inhibits invasive behavior of osteosarcoma cells through the inactivation of MAPK pathway. Cancer Manag Res. 2020;12:4949–55. doi: 10.2147/CMAR.S246928 32612383

105. Yanagawa SI, Lee JS, Ishimoto A. Identification and characterization of a novel line of Drosophila Schneider s2 cells that respond to wingless signaling. J Biol Chem. 1999;273:32353–9.

106. Wang J-W, Beck ES, McCabe BD. A modular toolset for recombination transgenesis and neurogenetic analysis of Drosophila. PLoS One. 2012;7:e42102. doi: 10.1371/journal.pone.0042102 22848718

107. Stormo BM, Fox DT. Distinct responses to reduplicated chromosomes require distinct Mad2 responses. elife. 2016;5. doi: 10.7554/eLife.15204 27159240

108. Puigbò P, Bravo IG, Garcia-Vallve S. CAIcal: A combined set of tools to assess codon usage adaptation. Biol Direct. 2008;3. doi: 10.1186/1745-6150-3-3 18226248

109. Thurmond J., Goodman J.L., Strelets V.B., Attrill H., Gramates L.S., Marygold S.J., et al. FlyBase 2.0: The next generation. Nucleic Acids Res. 47, D759–D765 (2019). doi: 10.1093/nar/gky1003 30364959

110. Quinlan AR, Hall IM. BEDTools: A flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–2. doi: 10.1093/bioinformatics/btq033 20110278

111. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Ser B. 1995;57:289–300.

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PLOS Genetics

2020 Číslo 12
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