A/Professor Thomas Preiss, PhDActing Head, Molecular Genetics Division
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Translation is an essential and tightly controlled step in gene expression. It takes place on the ribosome, and is aided by numerous accessory factors (figure 1). Dysregulation of translation is increasingly recognised as an important factor in human disease. Pathologic mechanisms may perturb the activity of components of the translational machinery with a broad impact on the cellular translation program, leading to, for instance, malignant transformation, inappropriate cell death or cardiac hypertrophy. Failure to properly regulate the translation of specific mRNAs is also linked to a growing spectrum of diseases.
The initiation phase of translation is a frequent target of regulatory intervention and represents all processes required for the assembly of a complete (80S) ribosome, consisting of the small (40S) and large (60S) subunit, at the start codon of the mRNA (figure 2). The scanning model describes the mechanism of initiation on a typical eukaryotic mRNA and features the translational adapter protein eIF4G as a central coordinator of 40S subunit recruitment to the mRNA. eIF4G interacts with the 5' cap structure and the 3' poly(A) tail of the mRNA, through the respective binding proteins eIF4E and PABP. Furthermore, eIF4G binds to the 40S-associated eIF3 and to the ATP-dependent RNA helicase eIF4A. We study the intricate mechanisms of initiating translation in yeast and mammalian cells using a combination of contemporary biochemical and genomic tools, including microarray technology (figure 3).
In yeast, we focus on the role of the mRNA poly(A) tail in gene expression. In general, a longer poly(A) tail leads to more efficient translation. We found clear differences in poly(A) tail length among the many thousand different mRNAs present in yeast cells and we are now trying to understand why this is so and how these differences in tail length affect the pattern of cellular protein synthesis.
Our work in mammalian cells is driven by two main research interests. One project looks at the translational changes that occur during induction of programmed cell death or apoptosis. Aberrant regulation of cell death contributes to many pathologies associated with cell loss (eg stroke, heart failure, neurodegeneration and AIDS), and disorders characterised by a failure to eliminate harmful cells (eg cancer, autoimmunity). We investigate specialised mechanisms of translation initiation that may be critical for maintaining a healthy balance between cell death and proliferation. The other project is looking at the effects of a new class of gene regulators called microRNAs. microRNAs are essential for stem cell differentiation and heart development, and are major players in cancer. We investigated how microRNAs control translation and discovered that they block functions of the Cap and Tail components of mRNA, and the Cap-binding factor eIF4E. We continue these mechanistic studies and in addition pursue the aim of identifying the mRNA targets of selected microRNAs
Co-Investigators:
Arash Araghi
Traude Beilharz, PhD
Jennifer Clancy, PhD
Claus Hallwirth, PhD
David Humphreys, PhD
Vanessa Schneider
Meghna Sobti, PhD
Jeffrey E Squires, PhD
Alex Shaw, BSc Hons
Grace (Heng) Wei, MSc
Jeni (Qiong Ni) Yuan, BSc Hons
Collaborators:
Dr Chris Brown, University of Otago, Dunedin, New Zealand
A/Prof Diane Fatkin, VCCRI, Sydney, Australia
Prof Richard Harvey, VCCRI, Sydney, Australia
A/Prof J?rg Heierhorst, SVI, Melbourne, Australia
Prof Joel Mackay, University of Sydney, Australia
Prof David Martin, VCCRI, Sydney, Australia
Dr Nigel McMillan, University of Queensland, Australia
Dr Cath Suter, VCCRI, Sydney, Australia
Dr Alex Swarbrick, Garvan Institute, Sydney, Australia
Selected Publications:
Preiss T, Hentze MW. Dual function of the messenger RNA cap structure in poly(A)-tail-promoted translation in yeast. Nature 1998; 392:516-520
Preiss T, Hentze MW. Starting the protein synthesis machine: eukaryotic translation initiation. BioEssays 2003; 25:1201-1211
Preiss T, Baron-Benhamou J, Ansorge W, Hentze MW. Homodirectional changes in transcriptome composition and translation induced by Rapamycin and heat shock. Nat Struct Biol 2003; 10:1039-1047
Humphreys DT, Westman B, Martin DIK, Preiss T. MicroRNAs control translation initiation by inhibiting eIF4E/cap and poly(A) tail function. Proc Natl Acad Sci (USA) 2005; 102:16961-6.
Nousch M, Reed V, Bryson-Richardson RJ, Currie PD, Preiss T. The eIF4G homologue p97 can activate translation independent of caspase cleavage. RNA 2007; 13:374-84.
Lackner DH, Beilharz TH, Marguerat S, Mata J, Watt S, Preiss T, Bahler J. A network of multiple regulatory layers shapes gene expression in fission yeast. Mol Cell 2007; 26:145-55.
Beilharz TH, Preiss T. Widespread use of poly(A) tail length control to accentuate expression of the yeast transcriptome. RNA 2007;13:982-97.
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