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Science 317 (5842): 1224-1227

Copyright © 2007 by the American Association for the Advancement of Science

Cap-Independent Translation Is Required for Starvation-Induced Differentiation in Yeast

Wendy V. Gilbert, Kaihong Zhou, Tamira K. Butler, Jennifer A. Doudna*

Abstract: Cellular internal ribosome entry sites (IRESs) are untranslated segments of mRNA transcripts thought to initiate protein synthesis in response to environmental stresses that prevent canonical 5' cap–dependent translation. Although numerous cellular mRNAs are proposed to have IRESs, none has a demonstrated physiological function or molecular mechanism. Here we show that seven yeast genes required for invasive growth, a developmental pathway induced by nutrient limitation, contain potent IRESs that require the initiation factor eIF4G for cap-independent translation. In contrast to the RNA structure-based activity of viral IRESs, we show that an unstructured A-rich element mediates internal initiation via recruitment of the poly(A) binding protein (Pab1) to the 5' untranslated region (UTR) of invasive growth messages. A 5'UTR mutation that impairs IRES activity compromises invasive growth, which indicates that cap-independent translation is required for physiological adaptation to stress.

Department of Molecular and Cell Biology, Department of Chemistry, and Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.

* To whom correspondence should be addressed. E-mail: doudna{at}

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S. Dvir, L. Velten, E. Sharon, D. Zeevi, L. B. Carey, A. Weinberger, and E. Segal (2013)
PNAS 110, E2792-E2801
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Roles for transcript leaders in translation and mRNA decay revealed by transcript leader sequencing.
J. A. Arribere and W. V. Gilbert (2013)
Genome Res. 23, 977-987
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Mol. Cell. Biol. 33, 307-318
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M. F. Rojas-Duran and W. V. Gilbert (2012)
RNA 18, 2299-2305
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DNA damage and eIF4G1 in breast cancer cells reprogram translation for survival and DNA repair mRNAs.
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PNAS 109, 18767-18772
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Global analysis reveals multiple pathways for unique regulation of mRNA decay in induced pluripotent stem cells.
A. T. Neff, J. Y. Lee, J. Wilusz, B. Tian, and C. J. Wilusz (2012)
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G. A. Brar, M. Yassour, N. Friedman, A. Regev, N. T. Ingolia, and J. S. Weissman (2012)
Science 335, 552-557
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The Regulation of Filamentous Growth in Yeast.
P. J. Cullen and G. F. Sprague Jr. (2012)
Genetics 190, 23-49
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Translational regulation of the cell cycle: when, where, how and why?.
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Phil Trans R Soc B 366, 3638-3652
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Protein Expression Regulation under Oxidative Stress.
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Translation Initiation: A Regulatory Role for Poly(A) Tracts in Front of the AUG Codon in Saccharomyces cerevisiae.
X. Xia, V. MacKay, X. Yao, J. Wu, F. Miura, T. Ito, and D. R. Morris (2011)
Genetics 189, 469-478
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Glucose depletion inhibits translation initiation via eIF4A loss and subsequent 48S preinitiation complex accumulation, while the pentose phosphate pathway is coordinately up-regulated.
L. M. Castelli, J. Lui, S. G. Campbell, W. Rowe, L. A. H. Zeef, L. E. A. Holmes, N. P. Hoyle, J. Bone, J. N. Selley, P. F. G. Sims, et al. (2011)
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Preference of IRES-mediated initiation of translation during hibernation in golden-mantled ground squirrels, Spermophilus lateralis.
P. Pan and F. van Breukelen (2011)
Am J Physiol Regulatory Integrative Comp Physiol 301, R370-R377
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5'TRU: Identification and Analysis of Translationally Regulative 5'Untranslated Regions in Amino Acid Starved Yeast Cells.
N. Rachfall, I. Heinemeyer, B. Morgenstern, O. Valerius, and G. H. Braus (2011)
Mol. Cell. Proteomics 10, M110.003350
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Noncanonical Translation Initiation of the Arabidopsis Flowering Time and Alternative Polyadenylation Regulator FCA.
G. G. Simpson, R. E. Laurie, P. P. Dijkwel, V. Quesada, P. A. Stockwell, C. Dean, and R. C. Macknight (2010)
PLANT CELL 22, 3764-3777
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Power of Yeast for Analysis of Eukaryotic Translation Initiation.
M. Altmann and P. Linder (2010)
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Alternative Ways to Think about Cellular Internal Ribosome Entry.
W. V. Gilbert (2010)
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Stress-Inducible Alternative Translation Initiation of Human Cytomegalovirus Latency Protein pUL138.
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J. Virol. 84, 9472-9486
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Systematic Epistasis Analysis of the Contributions of Protein Kinase A- and Mitogen-Activated Protein Kinase-Dependent Signaling to Nutrient Limitation-Evoked Responses in the Yeast Saccharomyces cerevisiae.
R. E. Chen and J. Thorner (2010)
Genetics 185, 855-870
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A possible mechanism for the regulation of IRES-mediated expression by eIF2A.
W. C. Merrick, L. C. Reineke, Y. Cao, and D. Baus (2010)
FASEB J 24, 467.5
Characterization of the functional role of nucleotides within the URE2 IRES element and the requirements for eIF2A-mediated repression.
L. C. Reineke and W. C. Merrick (2009)
RNA 15, 2264-2277
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RPS25 is essential for translation initiation by the Dicistroviridae and hepatitis C viral IRESs.
D. M. Landry, M. I. Hertz, and S. R. Thompson (2009)
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Translation initiation factors are not required for Dicistroviridae IRES function in vivo.
N. Deniz, E. M. Lenarcic, D. M. Landry, and S. R. Thompson (2009)
RNA 15, 932-946
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The Eukaryotic Ribosome: Current Status and Challenges.
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Cap-independent translation of human SP-A 5'-UTR variants: a double-loop structure and cis-element contribution.
G. Wang, X. Guo, P. Silveyra, S. R. Kimball, and J. Floros (2009)
Am J Physiol Lung Cell Mol Physiol 296, L635-L647
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N. E. Shirokikh and A. S. Spirin (2008)
PNAS 105, 10738-10743
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Translation initiation by the c-myc mRNA internal ribosome entry sequence and the poly(A) tail.
C. Thoma, S. Fraterman, M. Gentzel, M. Wilm, and M. W. Hentze (2008)
RNA 14, 1579-1589
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A Small Stem Loop Element Directs Internal Initiation of the URE2 Internal Ribosome Entry Site in Saccharomyces cerevisiae.
L. C. Reineke, A. A. Komar, M. G. Caprara, and W. C. Merrick (2008)
J. Biol. Chem. 283, 19011-19025
   Abstract »    Full Text »    PDF »

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