1932

Abstract

The conditional depletion of a protein of interest (POI) is useful not only for loss-of-function studies, but also for the modulation of biological pathways. Technologies that work at the level of DNA, mRNA, and protein are available for temporal protein depletion. Compared with technologies targeting the pretranslation steps, direct protein depletion (or protein knockdown approaches) is advantageous in terms of specificity, reversibility, and time required for depletion, which can be achieved by fusing a POI with a protein domain called a degron that induces rapid proteolysis of the fusion protein. Conditional degrons can be activated or inhibited by temperature, small molecules, light, or the expression of another protein. The conditional degron-based technologies currently available are described and discussed.

[Erratum, Closure]

An erratum has been published for this article:
Erratum: Conditional Degrons for Controlling Protein Expression at the Protein Level
Loading

Article metrics loading...

/content/journals/10.1146/annurev-genet-120116-024656
2017-11-27
2024-10-08
Loading full text...

Full text loading...

/deliver/fulltext/genet/51/1/annurev-genet-120116-024656.html?itemId=/content/journals/10.1146/annurev-genet-120116-024656&mimeType=html&fmt=ahah

Literature Cited

  1. Armstrong CM, Goldberg DE. 1.  2007. An FKBP destabilization domain modulates protein levels in Plasmodium falciparum. Nat. Methods 4:1007–9 [Google Scholar]
  2. Baker O, Gupta A, Obst M, Zhang Y, Anastassiadis K. 2.  et al. 2016. RAC-tagging: recombineering and Cas9-assisted targeting for protein tagging and conditional analyses. Sci. Rep. 6:25529 [Google Scholar]
  3. Banaszynski LA, Chen LC, Maynard-Smith LA, Ooi AGL, Wandless TJ. 3.  2006. A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules. Cell 126:995–1004This article described the first DD-based system using FKBP12 and its ligand, Shield-1. [Google Scholar]
  4. Banaszynski LA, Sellmyer MA, Contag CH, Wandless TJ, Thorne SH. 4.  2008. Chemical control of protein stability and function in living mice. Nat. Med. 14:1123–27 [Google Scholar]
  5. Bartel B, Wünning I, Varshavsky A. 5.  1990. The recognition component of the N-end rule pathway. EMBO J 9:3179–89 [Google Scholar]
  6. Bernal JA, Venkitaraman AR. 6.  2011. A vertebrate N-end rule degron reveals that Orc6 is required in mitosis for daughter cell abscission. J. Cell Biol. 192:969–78 [Google Scholar]
  7. Blattner AC, Chaurasia S, McKee BD, Lehner CF. 7.  2016. Separase is required for homolog and sister disjunction during Drosophila melanogaster male meiosis, but not for biorientation of sister centromeres. PLOS Genet 12:e1005996 [Google Scholar]
  8. Blomen VA, Májek P, Jae LT, Bigenzahn JW, Nieuwenhuis J. 8.  et al. 2015. Gene essentiality and synthetic lethality in haploid human cells. Science 350:1092–96 [Google Scholar]
  9. Bonger KM, Chen LC, Liu CW, Wandless TJ. 9.  2011. Small-molecule displacement of a cryptic degron causes conditional protein degradation. Nat. Chem. Biol. 7:531–37 [Google Scholar]
  10. Bonger KM, Rakhit R, Payumo AY, Chen JK, Wandless TJ. 10.  2014. General method for regulating protein stability with light. ACS Chem. Biol. 9:111–15The Wandless laboratory developed a light-induced degron system using the LOV2 domain and a synthetic degron. [Google Scholar]
  11. Brosh R, Hrynyk I, Shen J, Waghray A, Zheng N, Lemischka IR. 11.  2016. A dual molecular analogue tuner for dissecting protein function in mammalian cells. Nat. Commun. 7:11742 [Google Scholar]
  12. Buchberger A, Bukau B, Sommer T. 12.  2010. Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol. Cell 40:238–52 [Google Scholar]
  13. Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL. 13.  et al. 2015. HaloPROTACS: use of small molecule PROTACs to induce degradation of HaloTag fusion proteins. ACS Chem. Biol. 10:1831–37 [Google Scholar]
  14. Caussinus E, Affolter M. 14.  2016. deGradFP: a system to knockdown GFP-tagged proteins. Methods Mol. Biol. 1478:177–87 [Google Scholar]
  15. Caussinus E, Kanca O, Affolter M. 15.  2012. Fluorescent fusion protein knockout mediated by anti-GFP nanobody. Nat. Struct. Mol. Biol. 19:117–21This article described F-box fusion protein, the first system targeting GFP using a GFP-nanobody. [Google Scholar]
  16. Chapman EJ, Estelle M. 16.  2009. Mechanism of auxin-regulated gene expression in plants. Annu. Rev. Genet. 43:265–85 [Google Scholar]
  17. Cho U, Zimmerman SM, Chen LC, Owen E, Kim JV. 17.  et al. 2013. Rapid and tunable control of protein stability in Caenorhabditis elegans using a small molecule. PLOS ONE 8:e72393 [Google Scholar]
  18. Choi J, Chen J, Schreiber SL, Clardy J. 18.  1996. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273:239–42 [Google Scholar]
  19. Chung HK, Jacobs CL, Huo Y, Yang J, Krumm SA. 19.  et al. 2015. Tunable and reversible drug control of protein production via a self-excising degron. Nat. Chem. Biol. 11:713–20 [Google Scholar]
  20. Cong L, Ran FA, Cox D, Lin S, Barretto R. 20.  et al. 2013. Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–23 [Google Scholar]
  21. Daum G, Medzihradszky A, Suzaki T, Lohmann JU. 21.  2014. A mechanistic framework for noncell autonomous stem cell induction in Arabidopsis. PNAS 111:14619–24 [Google Scholar]
  22. Delacour Q, Li C, Plamont MA, Billon-Denis E, Aujard I. 22.  et al. 2015. Light-activated proteolysis for the spatiotemporal control of proteins. ACS Chem. Biol. 10:1643–47 [Google Scholar]
  23. Dharmasiri N, Dharmasiri S, Estelle M. 23.  2005. The F-box protein TIR1 is an auxin receptor. Nature 435:441–45 [Google Scholar]
  24. Dohmen RJ, Varshavsky A. 24.  2005. Heat-inducible degron and the making of conditional mutants. Methods Enzymol 399:799–822 [Google Scholar]
  25. Dohmen RJ, Wu P, Varshavsky A. 25.  1994. Heat-inducible degron: a method for constructing temperature-sensitive mutants. Science 263:1273–76This article reported the first conditional degron system, the ts-degron, in budding yeast. [Google Scholar]
  26. Egeler EL, Urner LM, Rakhit R, Liu CW, Wandless TJ. 26.  2011. Ligand-switchable substrates for a ubiquitin-proteasome system. J. Biol. Chem. 286:31328–36 [Google Scholar]
  27. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. 27.  2001. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–98 [Google Scholar]
  28. Erb MA, Scott TG, Li BE, Xie H, Paulk J. 28.  et al. 2017. Transcription control by the ENL YEATS domain in acute leukaemia. Nature 543:270–74 [Google Scholar]
  29. Faden F, Mielke S, Lange D, Dissmeyer N. 29.  2014. Generic tools for conditionally altering protein abundance and phenotypes on demand. Biol. Chem. 395:737–62 [Google Scholar]
  30. Faden F, Ramezani T, Mielke S, Almudi I, Nairz K. 30.  et al. 2016. Phenotypes on demand via switchable target protein degradation in multicellular organisms. Nat. Commun. 7:12202This article reported the development and use of the lt-degron in yeast, plants, and Drosophila. [Google Scholar]
  31. Fenno L, Yizhar O, Deisseroth K. 31.  2011. The development and application of optogenetics. Annu. Rev. Neurosci. 34:389–412 [Google Scholar]
  32. Fulcher LJ, Macartney T, Bozatzi P, Hornberger A, Rojas-Fernandez A, Sapkota GP. 32.  2016. An affinity-directed protein missile system for targeted proteolysis. Open Biol 6:160255 [Google Scholar]
  33. Gaj T, Sirk SJ, Shui SL, Liu J. 33.  2016. Genome-editing technologies: principles and applications. Cold Spring Harb. Perspect. Biol. 8:a023754 [Google Scholar]
  34. Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA. 34.  et al. 2013. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154:442–51 [Google Scholar]
  35. Glickman MH, Ciechanover A. 35.  2002. The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol. Rev. 82:373–428 [Google Scholar]
  36. Gossen M, Bujard H. 36.  1992. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. PNAS 89:5547–51 [Google Scholar]
  37. Gregan J, Lindner K, Brimage L, Franklin R, Namdar M. 37.  et al. 2003. Fission yeast Cdc23/Mcm10 functions after pre-replicative complex formation to promote Cdc45 chromatin binding. Mol. Biol. Cell 14:3876–87 [Google Scholar]
  38. Gronemeyer T, Godin G, Johnsson K. 38.  2005. Adding value to fusion proteins through covalent labelling. Curr. Opin. Biotechnol. 16:453–58 [Google Scholar]
  39. Harper SM, Neil LC, Gardner KH. 39.  2003. Structural basis of a phototropin light switch. Science 301:1541–44 [Google Scholar]
  40. Hart T, Chandrashekhar M, Aregger M, Steinhart Z, Brown KR. 40.  et al. 2015. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell 163:1515–26 [Google Scholar]
  41. Herm-Götz A, Agop-Nersesian C, Münter S, Grimley JS, Wandless TJ. 41.  et al. 2007. Rapid control of protein level in the apicomplexan Toxoplasma gondii. Nat. Methods 4:1003–5 [Google Scholar]
  42. Hermann A, Liewald JF, Gottschalk A. 42.  2015. A photosensitive degron enables acute light-induced protein degradation in the nervous system. Curr. Biol. 25:R749–50 [Google Scholar]
  43. Holland AJ, Fachinetti D, Han JS, Cleveland DW. 43.  2012. Inducible, reversible system for the rapid and complete degradation of proteins in mammalian cells. PNAS 109:E3350–57 [Google Scholar]
  44. Housden BE, Muhar M, Gemberling M, Gersbach CA, Stainier DY. 44.  et al. 2017. Loss-of-function genetic tools for animal models: cross-species and cross-platform differences. Nat. Rev. Genet. 18:24–40 [Google Scholar]
  45. Iwamoto M, Björklund T, Lundberg C, Kirik D, Wandless TJ. 45.  2010. A general chemical method to regulate protein stability in the mammalian central nervous system. Chem. Biol. 17:981–88 [Google Scholar]
  46. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J. 46.  et al. 2003. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotech 6:635–37 [Google Scholar]
  47. Jariel-Encontre I, Bossis G, Piechaczyk M. 47.  2008. Ubiquitin-independent degradation of proteins by the proteasome. Biochim. Biophys. Acta 1786:153–77 [Google Scholar]
  48. Johnsson N, Varshavsky A. 48.  1994. Split ubiquitin as a sensor of protein interactions in vivo. PNAS 91:10340–44 [Google Scholar]
  49. Jungbluth M, Renicke C, Taxis C. 49.  2010. Targeted protein depletion in Saccharomyces cerevisiae by activation of a bidirectional degron. BMC Syst. Biol. 4:176 [Google Scholar]
  50. Kaelin WG Jr. 50.  2012. Use and abuse of RNAi to study mammalian gene function. Science 337:421–22 [Google Scholar]
  51. Kanemaki M, Sanchez-Diaz A, Gambus A, Labib K. 51.  2003. Functional proteomic identification of DNA replication proteins by induced proteolysis in vivo. Nature 423:720–24 [Google Scholar]
  52. Kanke M, Nishimura K, Kanemaki M, Kakimoto T, Takahashi TS. 52.  et al. 2011. Auxin-inducible protein depletion system in fission yeast. BMC Cell Biol 12:8 [Google Scholar]
  53. Kearsey SE, Gregan J. 53.  2009. Using the DHFR heat-inducible degron for protein inactivation in Schizosaccharomyces pombe. Methods Mol. Biol. 521:483–92 [Google Scholar]
  54. Kepinski S, Leyser O. 54.  2005. The Arabidopsis F-box protein TIR1 is an auxin receptor. Nature 435:446–51 [Google Scholar]
  55. Kim JL, Morgenstern KA, Lin C, Fox T, Dwyer MD. 55.  et al. 1996. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87:343–55 [Google Scholar]
  56. Kreidenweiss A, Hopkins AV, Mordmüller B. 56.  2013. 2A and the auxin-based degron system facilitate control of protein levels in Plasmodium falciparum. PLOS ONE 8:e78661 [Google Scholar]
  57. Kubota T, Nishimura K, Kanemaki MT, Donaldson AD. 57.  2013. The Elg1 replication factor C-like complex functions in PCNA unloading during DNA replication. Mol. Cell 50:273–80 [Google Scholar]
  58. Labib K, Tercero JA, Diffley JFX. 58.  2000. Uninterrupted MCM2–7 function required for DNA replication fork progression. Science 288:1643–47 [Google Scholar]
  59. Lackner DH, Carré A, Guzzardo PM, Banning C, Mangena R. 59.  et al. 2015. A generic strategy for CRISPR-Cas9-mediated gene tagging. Nat. Commun. 6:10237 [Google Scholar]
  60. Lambrus BG, Uetake Y, Clutario KM, Daggubati V, Snyder M. 60.  et al. 2015. p53 protects against genome instability following centriole duplication failure. J. Cell Biol. 210:63–77 [Google Scholar]
  61. Le Y, Sauer B. 61.  2000. Conditional gene knockout using Cre recombinase. Methods Mol. Biol. 136:477–85 [Google Scholar]
  62. Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M. 62.  et al. 2016. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167:774–88.e17 [Google Scholar]
  63. Lindner K, Gregán J, Montgomery S, Kearsey SE. 63.  2002. Essential role of MCM proteins in premeiotic DNA replication. Mol. Biol. Cell 13:435–44 [Google Scholar]
  64. Liu KJ, Arron JR, Stankunas K, Crabtree GR, Longaker MT. 64.  2007. Chemical rescue of cleft palate and midline defects in conditional GSK-3β mice. Nature 446:79–82 [Google Scholar]
  65. Los GV, Encell LP, McDougall MG, Hartzell DD, Karassina N. 65.  et al. 2008. HaloTag: a novel protein labeling technology for cell imaging and protein analysis. ACS Chem. Biol. 3:373–82 [Google Scholar]
  66. Mali P, Yang L, Esvelt KM, Aach J, Guell M. 66.  et al. 2013. RNA-guided human genome engineering via Cas9. Science 339:823–26 [Google Scholar]
  67. Miller JC, Tan S, Qiao G, Barlow KA, Wang J. 67.  et al. 2011. A TALE nuclease architecture for efficient genome editing. Nat. Biotechnol. 29:143–48 [Google Scholar]
  68. Miyazaki Y, Imoto H, Chen LC, Wandless TJ. 68.  2012. Destabilizing domains derived from the human estrogen receptor. J. Am. Chem. Soc. 134:3942–45 [Google Scholar]
  69. Morawska M, Ulrich HD. 69.  2013. An expanded tool kit for the auxin-inducible degron system in budding yeast. Yeast 30:341–51 [Google Scholar]
  70. Muyldermans S. 70.  2013. Nanobodies: natural single-domain antibodies. Annu. Rev. Biochem. 82:775–97 [Google Scholar]
  71. Nakade S, Tsubota T, Sakane Y, Kume S, Sakamoto N. 71.  et al. 2014. Microhomology-mediated end-joining-dependent integration of donor DNA in cells and animals using TALENs and CRISPR/Cas9. Nat. Commun. 5:5560 [Google Scholar]
  72. Natsume T, Kiyomitsu T, Saga Y, Kanemaki MT. 72.  2016. Rapid protein depletion in human cells by auxin-inducible degron tagging with short homology donors. Cell Rep 15:210–18This article reported the combined use of AID and CRISPR–Cas9 to control endogenous proteins in human cells. [Google Scholar]
  73. Navarro R, Chen LC, Rakhit R, Wandless TJ. 73.  2016. A novel destabilizing domain based on a small-molecule dependent fluorophore. ACS Chem. Biol. 11:2101–4 [Google Scholar]
  74. Neklesa TK, Tae HS, Schneekloth AR, Stulberg MJ, Corson TW. 74.  et al. 2011. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nat. Chem. Biol. 7:538–43This article reported the first use of the HaloTag for targeted proteolysis. [Google Scholar]
  75. Nishimura K, Fukagawa T, Takisawa H, Kakimoto T, Kanemaki M. 75.  2009. An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat. Methods 6:917–22 [Google Scholar]
  76. Nishimura K, Kanemaki MT. 76.  2014. Rapid depletion of budding yeast proteins via the fusion of an auxin-inducible degron (AID). Curr. Protoc. Cell Biol. 64:20.9.1–16This article was the first to describe AID technology and its use in yeast and mammalian cells. [Google Scholar]
  77. Niwa T, Ise M, Miyazaki T. 77.  1994. Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate. Am. J. Nephrol. 14:207–12 [Google Scholar]
  78. Ohana RF, Encell LP, Zhao K, Simpson D, Slater MR. 78.  et al. 2009. HaloTag7: a genetically engineered tag that enhances bacterial expression of soluble proteins and improves protein purification. Protein Expr. Purif. 68:110–20 [Google Scholar]
  79. Ouellet F, Overvoorde PJ, Theologis A. 79.  2001. IAA17/AXR3: biochemical insight into an auxin mutant phenotype. Plant Cell 13:829–41 [Google Scholar]
  80. Park A, Won ST, Pentecost M, Bartkowski W, Lee B. 80.  2014. CRISPR/Cas9 allows efficient and complete knock-in of a destabilization domain-tagged essential protein in a human cell line, allowing rapid knockdown of protein function. PLOS ONE 9:e95101 [Google Scholar]
  81. Patten CL, Glick BR. 81.  1996. Bacterial biosynthesis of indole-3-acetic acid. Can. J. Microbiol. 42:207–20 [Google Scholar]
  82. Philip N, Waters AP. 82.  2015. Conditional degradation of Plasmodium calcineurin reveals functions in parasite colonization of both host and vector. Cell Host Microbe 18:122–31 [Google Scholar]
  83. Porteus M. 83.  2008. Design and testing of zinc finger nucleases for use in mammalian cells. Methods Mol. Biol. 435:47–61 [Google Scholar]
  84. Potuschak T, Stary S, Schlögelhofer P, Becker F, Nejinskaia V, Bachmair A. 84.  1998. PRT1 of Arabidopsis thaliana encodes a component of the plant N-end rule pathway. PNAS 95:7904–8 [Google Scholar]
  85. Pratt MR, Schwartz EC, Muir TW. 85.  2007. Small-molecule-mediated rescue of protein function by an inducible proteolytic shunt. PNAS 104:11209–14 [Google Scholar]
  86. Rajagopalan S, Liling Z, Liu J, Balasubramanian M. 86.  2004. The N-degron approach to create temperature-sensitive mutants in Schizosaccharomyces pombe. Methods 33:206–12 [Google Scholar]
  87. Rakhit R, Edwards SR, Iwamoto M, Wandless TJ. 87.  2011. Evaluation of FKBP and DHFR based destabilizing domains in Saccharomyces cerevisiae. Bioorg. Med. Chem. Lett 214965–68 [Google Scholar]
  88. Reed JW. 88.  2001. Roles and activities of Aux/IAA proteins in Arabidopsis. Trends Plant Sci 6:420–25 [Google Scholar]
  89. Renicke C, Schuster D, Usherenko S, Essen LO, Taxis C. 89.  2013. A LOV2 domain-based optogenetic tool to control protein degradation and cellular function. Chem. Biol. 20:619–26The Taxis laboratory developed a light-induced degron system using the LOV2 domain and an ODC-degron. [Google Scholar]
  90. Rodriguez S, Wolfgang MJ. 90.  2012. Targeted chemical-genetic regulation of protein stability in vivo. Chem. Biol. 19:391–98 [Google Scholar]
  91. Sacher R, Stergiou L, Pelkmans L. 91.  2008. Lessons from genetics: interpreting complex phenotypes in RNAi screens. Curr. Opin. Cell Biol. 20:483–89 [Google Scholar]
  92. Sakamoto KM. 92.  2010. Protacs for treatment of cancer. Pediatr. Res. 67:505–8 [Google Scholar]
  93. Sanchez-Diaz A, Kanemaki M, Marchesi V, Labib K. 93.  2004. Rapid depletion of budding yeast proteins by fusion to a heat-inducible degron. Sci. STKE 2004:PL8 [Google Scholar]
  94. Sanchez-Diaz A, Marchesi V, Murray S, Jones R, Pereira G. 94.  et al. 2008. Inn1 couples contraction of the actomyosin ring to membrane ingression during cytokinesis in budding yeast. Nat. Cell Biol. 10:395–406 [Google Scholar]
  95. Sauer B, Henderson N. 95.  1988. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. PNAS 85:5166–70 [Google Scholar]
  96. Schneekloth JS Jr., Fonseca FN, Koldobskiy M, Mandal A, Deshaies R. 96.  et al. 2004. Chemical genetic control of protein levels: selective in vivo targeted degradation. J. Am. Chem. Soc. 126:3748–54 [Google Scholar]
  97. Sheard LB, Tan X, Mao H, Withers J, Ben-Nissan G. 97.  et al. 2010. Jasmonate perception by inositol-phosphate-potentiated COI1–JAZ co-receptor. Nature 468:400–5 [Google Scholar]
  98. Sheridan RM, Bentley DL. 98.  2016. Selectable one-step PCR-mediated integration of a degron for rapid depletion of endogenous human proteins. Biotechniques 60:69–74 [Google Scholar]
  99. Shin YJ, Park SK, Jung YJ, Kim YN, Kim KS. 99.  et al. 2015. Nanobody-targeted E3–ubiquitin ligase complex degrades nuclear proteins. Sci. Rep. 5:14269 [Google Scholar]
  100. Spartz AK, Gray WM. 100.  2008. Plant hormone receptors: new perceptions. Genes Dev 22:2139–48 [Google Scholar]
  101. Stankunas K, Bayle JH, Gestwicki JE, Lin YM, Wandless TJ, Crabtree GR. 101.  2003. Conditional protein alleles using knockin mice and a chemical inducer of dimerization. Mol. Cell 12:1615–24 [Google Scholar]
  102. Su L, Li A, Li H, Chu C, Qiu JL. 102.  2013. Direct modulation of protein level in Arabidopsis. Mol. Plant 6:1711–14 [Google Scholar]
  103. Su X, Bernal JA, Venkitaraman AR. 103.  2008. Cell-cycle coordination between DNA replication and recombination revealed by a vertebrate N-end rule degron-Rad51. Nat. Struct. Mol. Biol. 15:1049–58 [Google Scholar]
  104. Suzuki T, Varshavsky A. 104.  1999. Degradation signals in the lysine–asparagine sequence space. EMBO J 18:6017–26 [Google Scholar]
  105. Tae HS, Sundberg TB, Neklesa TK, Noblin DJ, Gustafson JL. 105.  et al. 2012. Identification of hydrophobic tags for the degradation of stabilized proteins. ChemBioChem 13:538–41 [Google Scholar]
  106. Tan X, Calderon-Villalobos LIA, Sharon M, Zheng C, Robinson CV. 106.  et al. 2007. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature 446:640–45 [Google Scholar]
  107. Tasaki T, Sriram SM, Park KS, Kwon YT. 107.  2012. The N-end rule pathway. Annu. Rev. Biochem. 81:261–89 [Google Scholar]
  108. Taxis C, Knop M. 108.  2012. TIPI: TEV protease-mediated induction of protein instability. Methods Mol. Biol. 832:611–26 [Google Scholar]
  109. Taxis C, Stier G, Spadaccini R, Knop M. 109.  2009. Efficient protein depletion by genetically controlled deprotection of a dormant N-degron. Mol. Syst. Biol. 5:267This article was the first to describe TIPI-degron, used in yeast. [Google Scholar]
  110. Teng X, Dayhoff-Brannigan M, Cheng WC, Gilbert CE, Sing CN. 110.  et al. 2013. Genome-wide consequences of deleting any single gene. Mol. Cell 52:485–94 [Google Scholar]
  111. Thines B, Katsir L, Melotto M, Niu Y, Mandaokar A. 111.  et al. 2007. JAZ repressor proteins are targets of the SCFCOI1 complex during jasmonate signalling. Nature 448:661–65 [Google Scholar]
  112. Tomoshige S, Naito M, Hashimoto Y, Ishikawa M. 112.  2015. Degradation of HaloTag-fused nuclear proteins using bestatin–HaloTag ligand hybrid molecules. Org. Biomol. Chem. 13:9746–50 [Google Scholar]
  113. Trost M, Blattner AC, Lehner CF. 113.  2016. Regulated protein depletion by the auxin-inducible degradation system in Drosophila melanogaster. Fly 10:35–46 [Google Scholar]
  114. Urban E, Nagarkar-Jaiswal S, Lehner CF, Heidmann SK. 114.  2014. The cohesin subunit Rad21 is required for synaptonemal complex maintenance, but not sister chromatid cohesion, during Drosophila female meiosis. PLOS Genet 10:e1004540 [Google Scholar]
  115. Usherenko S, Stibbe H, Muscó M, Essen LO, Kostina EA, Taxis C. 115.  2014. Photo-sensitive degron variants for tuning protein stability by light. BMC Syst. Biol. 8:128 [Google Scholar]
  116. Varshavsky A. 116.  1991. Naming a targeting signal. Cell 64:13–15 [Google Scholar]
  117. Varshavsky A. 117.  2011. The N-end rule pathway and regulation by proteolysis. Protein Sci 20:1298–345 [Google Scholar]
  118. Wang T, Wei JJ, Sabatini DM, Lander ES. 118.  2014. Genetic screens in human cells using the CRISPR–Cas9 system. Science 343:80–84 [Google Scholar]
  119. Weiss WA, Taylor SS, Shokat KM. 119.  2007. Recognizing and exploiting differences between RNAi and small-molecule inhibitors. Nat. Chem. Biol. 3:739–44 [Google Scholar]
  120. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A. 120.  et al. 2015. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348:1376–81 [Google Scholar]
  121. Wood L, Booth DG, Vargiu G, Ohta S, deLima Alves F. 121.  et al. 2016. Auxin/AID versus conventional knockouts: distinguishing the roles of CENP-T/W in mitotic kinetochore assembly and stability. Open Biol 6:150230 [Google Scholar]
  122. Zhang L, Ward JD, Cheng Z, Dernburg AF. 122.  2015. The auxin-inducible degradation (AID) system enables versatile conditional protein depletion in C. elegans. Development 142:4374–84 [Google Scholar]
  123. Zhao Y. 123.  2010. Auxin biosynthesis and its role in plant development. Annu. Rev. Plant Biol. 61:49–64 [Google Scholar]
  124. Zhou P. 124.  2005. Targeted protein degradation. Curr. Opin. Chem. Biol. 9:51–55 [Google Scholar]
  125. Zhou P, Bogacki R, McReynolds L, Howley PM. 125.  2000. Harnessing the ubiquitination machinery to target the degradation of specific cellular proteins. Mol. Cell 6:751–56 [Google Scholar]
/content/journals/10.1146/annurev-genet-120116-024656
Loading
/content/journals/10.1146/annurev-genet-120116-024656
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error