1887

Abstract

Transcriptional elongation is a critical step for regulating expression of protein-coding genes. Multiple transcription elongation factors have been identified , but the physiological roles of many of them are still not clearly understood. The ELL (Eleven nineteen Lysine rich Leukemia) family of transcription elongation factors are conserved from fission yeast to humans. contains a single ELL homolog (SpELL) that is not essential for its survival. Therefore to gain insights into the cellular functions of SpELL, we identified phenotypes associated with deletion of in . Our results demonstrate that SpELL is required for normal growth of cells. Furthermore, cells lacking exhibit a decrease in survival when exposed to DNA-damaging conditions, but their growth is not affected under environmental stress conditions. ELL orthologs in different organisms contain three conserved domains, an amino-terminal domain, a middle domain and a carboxyl-terminal domain. We also carried out an functional mapping of these conserved domains within ELL and uncovered a critical role for its amino-terminus in regulating all its cellular functions, including growth under different conditions, transcriptional elongation potential and interaction with EAF. Taken together our results suggest that the domain organization of ELL proteins is conserved across species, but the functions as well as the relationship between the various domains and roles of ELL show species-specific differences.

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2017-11-01
2024-04-16
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References

  1. Zhou Q, Li T, Price DH. RNA polymerase II elongation control. Annu Rev Biochem 2012; 81:119–143 [View Article][PubMed]
    [Google Scholar]
  2. Kwak H, Lis JT. Control of transcriptional elongation. Annu Rev Genet 2013; 47:483–508 [View Article][PubMed]
    [Google Scholar]
  3. Shilatifard A. Factors regulating the transcriptional elongation activity of RNA polymerase II. FASEB J 1998; 12:1437–1446[PubMed]
    [Google Scholar]
  4. Sharma N. Regulation of RNA polymerase II-mediated transcriptional elongation: implications in human disease. IUBMB Life 2016; 68:709–716 [View Article][PubMed]
    [Google Scholar]
  5. Shilatifard A, Lane WS, Jackson KW, Conaway RC, Conaway JW. An RNA polymerase II elongation factor encoded by the human ELL gene. Science 1996; 271:1873–1876 [View Article][PubMed]
    [Google Scholar]
  6. Shilatifard A, Duan DR, Haque D, Florence C, Schubach WH et al. ELL2, a new member of an ELL family of RNA polymerase II elongation factors. Proc Natl Acad Sci USA 1997; 94:3639–3643 [View Article][PubMed]
    [Google Scholar]
  7. Miller T, Williams K, Johnstone RW, Shilatifard A. Identification, cloning, expression, and biochemical characterization of the testis-specific RNA polymerase II elongation factor ELL3. J Biol Chem 2000; 275:32052–32056 [View Article][PubMed]
    [Google Scholar]
  8. Thirman MJ, Levitan DA, Kobayashi H, Simon MC, Rowley JD. Cloning of ELL, a gene that fuses to MLL in at (11;19)(q23;p13.1) in acute myeloid leukemia. Proc Natl Acad Sci USA 1994; 91:12110–12114 [View Article][PubMed]
    [Google Scholar]
  9. Simone F, Polak PE, Kaberlein JJ, Luo RT, Levitan DA et al. EAF1, a novel ELL-associated factor that is delocalized by expression of the MLL-ELL fusion protein. Blood 2001; 98:201–209 [View Article][PubMed]
    [Google Scholar]
  10. Simone F, Luo RT, Polak PE, Kaberlein JJ, Thirman MJ. ELL-associated factor 2 (EAF2), a functional homolog of EAF1 with alternative ELL binding properties. Blood 2003; 101:2355–2362 [View Article][PubMed]
    [Google Scholar]
  11. Kong SE, Banks CA, Shilatifard A, Conaway JW, Conaway RC. ELL-associated factors 1 and 2 are positive regulators of RNA polymerase II elongation factor ELL. Proc Natl Acad Sci USA 2005; 102:10094–10098 [View Article][PubMed]
    [Google Scholar]
  12. Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell 2010; 37:429–437 [View Article][PubMed]
    [Google Scholar]
  13. Smith ER, Lin C, Garrett AS, Thornton J, Mohaghegh N et al. The little elongation complex regulates small nuclear RNA transcription. Mol Cell 2011; 44:954–965 [View Article][PubMed]
    [Google Scholar]
  14. Shilatifard A, Haque D, Conaway RC, Conaway JW. Structure and function of RNA polymerase II elongation factor ELL. Identification of two overlapping ELL functional domains that govern its interaction with polymerase and the ternary elongation complex. J Biol Chem 1997; 272:22355–22363[PubMed] [Crossref]
    [Google Scholar]
  15. Luo RT, Lavau C, Du C, Simone F, Polak PE et al. The elongation domain of ELL is dispensable but its ELL-associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis. Mol Cell Biol 2001; 21:5678–5687 [View Article][PubMed]
    [Google Scholar]
  16. DiMartino JF, Miller T, Ayton PM, Landewe T, Hess JL et al. A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. Blood 2000; 96:3887–3893[PubMed]
    [Google Scholar]
  17. Johnstone RW, Gerber M, Landewe T, Tollefson A, Wold WS et al. Functional analysis of the leukemia protein ELL: evidence for a role in the regulation of cell growth and survival. Mol Cell Biol 2001; 21:1672–1681 [View Article][PubMed]
    [Google Scholar]
  18. Chen Y, Zhou C, Ji W, Mei Z, Hu B et al. ELL targets c-Myc for proteasomal degradation and suppresses tumour growth. Nat Commun 2016; 7:11057 [View Article][PubMed]
    [Google Scholar]
  19. Eissenberg JC, Ma J, Gerber MA, Christensen A, Kennison JA et al. dELL is an essential RNA polymerase II elongation factor with a general role in development. Proc Natl Acad Sci USA 2002; 99:9894–9899 [View Article][PubMed]
    [Google Scholar]
  20. Gerber M, Ma J, Dean K, Eissenberg JC, Shilatifard A et al. Drosophila ELL is associated with actively elongating RNA polymerase II on transcriptionally active sites in vivo. EMBO J 2001; 20:6104–6114 [View Article][PubMed]
    [Google Scholar]
  21. Cai L, Phong BL, Fisher AL, Wang Z. Regulation of fertility, survival, and cuticle collagen function by the Caenorhabditis elegans eaf-1 and ell-1 genes. J Biol Chem 2011; 286:35915–35921 [View Article][PubMed]
    [Google Scholar]
  22. Smith ER, Winter B, Eissenberg JC, Shilatifard A. Regulation of the transcriptional activity of poised RNA polymerase II by the elongation factor ELL. Proc Natl Acad Sci USA 2008; 105:8575–8579 [View Article][PubMed]
    [Google Scholar]
  23. Gerber MA, Shilatifard A, Eissenberg JC. Mutational analysis of an RNA polymerase II elongation factor in Drosophila melanogaster . Mol Cell Biol 2005; 25:7803–7811 [View Article][PubMed]
    [Google Scholar]
  24. Sakurai K, Michiue T, Kikuchi A, Asashima M. Inhibition of the canonical Wnt signaling pathway in cytoplasm: a novel property of the carboxyl terminal domains of two Xenopus ELL genes. Zoolog Sci 2004; 21:407–416 [View Article][PubMed]
    [Google Scholar]
  25. Banks CA, Kong SE, Spahr H, Florens L, Martin-Brown S et al. Identification and characterization of a Schizosaccharomyces pombe RNA polymerase II elongation factor with similarity to the metazoan transcription factor ELL. J Biol Chem 2007; 282:5761–5769 [View Article][PubMed]
    [Google Scholar]
  26. Gregan J, Rabitsch PK, Sakem B, Csutak O, Latypov V et al. Novel genes required for meiotic chromosome segregation are identified by a high-throughput knockout screen in fission yeast. Curr Biol 2005; 15:1663–1669 [View Article][PubMed]
    [Google Scholar]
  27. Cokol M, Nair R, Rost B. Finding nuclear localization signals. EMBO Rep 2000; 1:411–415 [View Article][PubMed]
    [Google Scholar]
  28. Gassman NR, Clodfelter JE, McCauley AK, Bonin K, Salsbury FR et al. Cooperative nuclear localization sequences lend a novel role to the N-terminal region of MSH6. PLoS One 2011; 6:1 [View Article]
    [Google Scholar]
  29. Kosugi S, Hasebe M, Tomita M, Yanagawa H. Systematic identification of cell cycle-dependent yeast nucleocytoplasmic shuttling proteins by prediction of composite motifs. Proc Natl Acad Sci USA 2009; 106:10171–10176 [View Article][PubMed]
    [Google Scholar]
  30. Pagni M, Loannidis V, Cerutti L, Zahn-Zabal M, Jongeneel CV et al. MyHits: improvements to an interactive resource for analyzing protein sequences. Nucleic Acids Res 2007; 35:W433–W437 [View Article]
    [Google Scholar]
  31. Jones DT. Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 1999; 292:195–202 [View Article][PubMed]
    [Google Scholar]
  32. Sickmeier M, Hamilton JA, LeGall T, Vacic V, Cortese MS et al. DisProt: the database of disordered proteins. Nucleic Acids Res 2007; 35:D786–D793 [View Article][PubMed]
    [Google Scholar]
  33. Yang ZR, Thomson R, McNeil P, Esnouf RM. RONN: the bio-basis function neural network technique applied to the detection of natively disordered regions in proteins. Bioinformatics 2005; 21:3369–3376 [View Article][PubMed]
    [Google Scholar]
  34. Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN et al. PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta 2010; 1804:996–1010 [View Article][PubMed]
    [Google Scholar]
  35. Bonfils S, Rozalén AE, Smith GR, Moreno S, Martín-Castellanos C et al. Functional interactions of Rec24, the fission yeast ortholog of mouse Mei4, with the meiotic recombination-initiation complex. J Cell Sci 2011; 124:1328–1338 [View Article][PubMed]
    [Google Scholar]
  36. Donovan S, Harwood J, Drury LS, Diffley JF. Cdc6p-dependent loading of Mcm proteins onto pre-replicative chromatin in budding yeast. Proc Natl Acad Sci USA 1997; 94:5611–5616 [View Article][PubMed]
    [Google Scholar]
  37. Arora C, Kee K, Maleki S, Keeney S. Antiviral protein Ski8 is a direct partner of Spo11 in meiotic DNA break formation, independent of its cytoplasmic role in RNA metabolism. Mol Cell 2004; 13:549–559 [View Article][PubMed]
    [Google Scholar]
  38. Kosugi S, Hasebe M, Matsumura N, Takashima H, Miyamoto-Sato E et al. Six classes of nuclear localization signals specific to different binding grooves of importin alpha. J Biol Chem 2009; 284:478–485 [View Article][PubMed]
    [Google Scholar]
  39. Shilatifard A, Conaway RC, Conaway JW. The RNA polymerase II elongation complex. Annu Rev Biochem 2003; 72:693–715 [View Article][PubMed]
    [Google Scholar]
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