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Dr Tobias von der Haar

Reader in Systems Biology/Director of Research

School of Biosciences

 

Dr Tobias von der Haar joined the School of Biosciences in 2005. He is a member of the Centre for Molecular Processing, the Yeast Molecular Biology Group and the Kent Fungal Group.

Degrees Held

1995 - Undergraduate Studies, University of Bielefeld, Germany
1998 - PhD, jointly at the German National Biotechnology Centre (GBF), Braunschweig, Germany; and at UMIST, Manchester, UK.

Research Career

1998-2004

Postdoctoral Work at UMIST, Manchester

2004-2005

Postdoctoral Work at the University of Kent

2005-2009

Wellcome Trust Research Career Development Fellowship at the University of Kent

2009-present Lecturer in Systems Biology, University of Kent

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Also view these in the Kent Academic Repository

Article
von der Haar, T. et al. (2017). The control of translational accuracy is a determinant of healthy ageing in yeast. Open Biology [Online] 7:160291. Available at: http://dx.doi.org/10.1098/rsob.160291.
Saintas, E. et al. (2017). Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS. PLoS ONE [Online] 12:e0172140. Available at: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172140.
Bastide, A. et al. (2017). RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3. Current Biology [Online] 27:638-650. Available at: https://doi.org/10.1016/j.cub.2017.01.047.
Saintas, E. et al. (2017). Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS. PloS one [Online] 12:e0172140. Available at: http://dx.doi.org/10.1371/journal.pone.0172140.
Tuite, M. and von der Haar, T. (2016). Transfer RNA in Decoding and the Wobble Hypothesis. eLS [Online]:1-7. Available at: http://doi.org/10.1002/9780470015902.a0001497.pub2.
Tarrant, D. et al. (2016). Inappropriate expression of the translation elongation factor 1A disrupts genome stability and metabolism. Journal of Cell Science [Online] 129:4455-4465. Available at: http://doi.org/10.1242/jcs.192831.
Beznoskova, P. et al. (2015). Translation initiation factor eIF3 promotes programmed stop codon readthrough. Nucleic Acids Research [Online] 43:5099-5111. Available at: http://nar.oxfordjournals.org/content/43/10/5099.
Blanchet, S. et al. (2015). New insights into stop codon recognition by eRF1. Nucleic Acids Research [Online] 43:3298-3308. Available at: http://dx.doi.org/10.1093/nar/gkv154.
Blanchet, S. et al. (2015). New insights into stop codon recognition by eRF1. Nucleic Acids Research [Online] 43:3298-3308. Available at: http://dx.doi.org/10.1093/nar/gkv154.
Bill, R. and von der Haar, T. (2015). Hijacked then lost in translation: the plight of the recombinant host cell in membrane protein structural biology projects. Current Opinion in Structural Biology [Online] 32:147-155. Available at: http://doi.org/10.1016/j.sbi.2015.04.003.
Tarrant, D. and von der Haar, T. (2014). Synonymous codons, ribosome speed, and eukaryotic gene expression regulation. Cellular and Molecular Life Sciences [Online] 71:4195-4206. Available at: http://dx.doi.org/10.1007/s00018-014-1684-2.
von der Haar, T. and Kazana, E. (2014). The translational machinery is an optimized molecular network that affects cellular homoeostasis and disease. Biochemical Society Transactions [Online] 42:173-176. Available at: http://dx.doi.org/10.1042/BST20130131.
Chu, D., Thompson, J. and von der Haar, T. (2014). Charting the dynamics of translation. Bio Systems [Online] 119:1-9. Available at: http://dx.doi.org/10.1016/j.biosystems.2014.02.005.
Mead, E. et al. (2014). Control and regulation of mRNA translation. Biochemical Society Transactions [Online] 42:151-154. Available at: http://dx.doi.org/10.1042/BST20130259.
Beznoskova, P. et al. (2013). Translation Initiation Factors eIF3 and HCR1 Control Translation Termination and Stop Codon Read-Through in Yeast Cells . PLoS Genetics [Online] 9:e1003962. Available at: http://dx.doi.org/10.1371/journal.pgen.1003962.
Hopker, J. et al. (2013). The influence of training status, age, and muscle fiber type on cycling efficiency and endurance performance. Journal of Applied Physiology [Online] 115:723-729. Available at: http://dx.doi.org/10.1152/japplphysiol.00361.2013.
Preiss, T. et al. (2013). Specialized Yeast Ribosomes: A Customized Tool for Selective mRNA Translation. PLoS ONE [Online] 8:e67609. Available at: http://dx.doi.org/10.1371/journal.pone.0067609.
Chu, D. et al. (2013). Translation elongation can control translation initiation on eukaryotic mRNAs. EMBO Journal [Online] 33:21-34. Available at: http://dx.doi.org/10.1002/embj.201385651.
von der Haar, T. (2012). Mathematical and Computational Modelling of Ribosomal Movement and Protein Synthesis: an overview. Computational and Structural Biotechnology Journal [Online] 1:e201204002. Available at: http://dx.doi.org/10.5936/csbj.201204002.
Jossé, L. et al. (2012). Probing the role of structural features of mouse PrP in yeast by expression as Sup35-PrP fusions. Prion [Online] 6:201-210. Available at: http://dx.doi.org/10.4161/pri.19214.
Chu, D., Zabet, N. and von der Haar, T. (2012). A novel and versatile computational tool to model translation. Bioinformatics [Online] 28:292-293. Available at: http://dx.doi.org/10.1093/bioinformatics/btr650.
Mead, E. et al. (2012). Experimental and In Silico Modelling Analyses of the Gene Expression Pathway for Recombinant Antibody and By-Product Production in NS0 Cell Lines. PLoS ONE [Online] 7:e47422. Available at: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047422.
Book section
von der Haar, T. and Valasek, L. (2014). mRNA Translation: Fungal Variations on a Eukaryotic Theme. in: Sesma, A. and von der Haar, T. eds. Fungal RNA Biology. Springer International Publishing, pp. 113-134. Available at: http://dx.doi.org/10.1007/978-3-319-05687-6_5.
Thesis
Ji, H. (2015). Fibrinolytic Regulation of Pulmonary Epithelial Sodium Channels: a Critical Review.
Edited book
Sesma, A. and von der Haar, T. eds. (2014). Fungal RNA Biology. [Online]. Springer International Publishing. Available at: http://www.springer.com/gb/book/9783319056869.
Showing 25 of 47 total publications in KAR. [See all in KAR]

 

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Regulation of gene expression at a translational level

The processes that allow a cell to live rely on a particular mixture of proteins, the proteome, being present in the cell at any given time. The individual proteins making up the proteome are constantly diluted by cell divisions and lost because of protein turnover. In order to maintain a functional proteome and stay alive, cells must therefore constantly produce new proteins, with required rates of synthesis that may differ significantly between gene products. Moreover, the synthesis of an entirely different set of proteins may be required when environmental conditions change.

Eukaryotic gene expression relies on an ordered sequence of molecular events: First, a stretch of DNA containing a gene is transcribed into a messenger RNA molecule, this is then processed to its final form and exported from the nucleus to the cytoplasm. Ribosomes bind to the cytoplasmic mRNA with the help of translation initiation factors, and then (with the help of translation elongation and termination factors and tRNAs) assemble the protein from amino acids according to the genetic information encoded in the mRNA. The mRNA itself is destroyed after a short while, typically after about 1000 proteins have been produced from it.

protein synthesis

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



If the rate of production of one particular gene product needs to be altered by the cell, any of the steps of gene expression can be targeted: for example, the rate of transcription may be adjusted, or the proportion of RNAs that are exported from the nucleus, or the rate with which ribosomes produce protein from the cytoplasmic mRNA. We are particularly interested in the latter form of control; the production of varying amounts of protein from the same amount of mRNA.

The motivation for our interest in this question comes from the need to understand in detail the mechanism by which cells live, develop and adapt to changing environmental conditions, in order to understand what goes wrong when diseases prevent cells from achieving these feats.

Current Projects:

The molecular mechanism of translation termination

Translation termination is the last step in the overall process of translation, in which the newly synthesized protein is released from the ribosome:mRNA complex. It occurs when any one of the three stop codons UAA, UAG or UGA enter the decoding centre in the ribosomal A-site. Unlike sense codons, stop codons are not decoded by transfer RNAS but are instead acted on by the translation release factors (RFs in bacteria, or eRFs in eukaryotes).
A currently established minimal model for the mechanism of translation termination includes the following steps:

  • A ternary complex forms between the two types of release factor (eRF1 and eRF3) and GTP.
  • The ternary complex enters the ribosomal A-site.
  • If the codon in the A-site is a stop codon, the GTP in the complex is hydrolysed to GDP, resulting in a conformational re-arrangement of the release factors and/ or the ribosome, severing of the P-site tRNA-peptidyl bond, and release of the newly translated peptide from the ribosome.

This relatively simple model incorporates many of the published data that address the process of translation termination. However, in yeast mutations in many genes apart from the two eRF-encoding genes affect translation termination efficiency, and it is currently not clear how the proteins encoded by those genes are involved in the termination reaction. Conversely, mutations that affect translation termination almost always also affect the stability of mRNAs, consistent with known interactions between the two processes of termination and mRNA turnover. Again, it is not clear at a molecular level how these processes interact

translation termination

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

We are using general molecular biology techniques to investigate both in vivo and in vitro the molecular details of the mechanism of translation termination.

 

Cellular consequences of impaired translation termination

Efficient translation termination is essential for the production of all proteins. However, because different stop codons have different termination efficiencies depending on their sequence context, reductions in translation termination efficiency can affect the production of one protein much more than the production of another. Relatively small reductions in translation termination efficiency will therefore have significant impact on the composition of the proteome. Moreover, because of the close connection between translation termination and mRNA turnover, this may be exacerbated by additional differential effects on mRNA stability.

translation termination efficiency

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Small imbalances in the proteome are difficult to measure directly, but may become clearly evident through cellular phenotypes: for example, a small reduction in the activity of a factor involved in the adaptation to osmotic stress may not be easily visible at the protein level, but may become obvious because the cells can adopt less well to high osmolarity conditions. We are using this approach of looking for translation termination-factor dependent phenotypes to identify processes that may be specifically targeted when translation termination activity becomes impaired, and to search for potential novel, non-translational roles of the termination factors in the cell.

 

Mathematical models of translation termination in vivo

Interactions between translation termination, mRNA decay and the composition of the proteome are very complex and only poorly understood. This complexity makes it currently impossible to predict the effect that changes in translation termination efficiency have on any particular protein. In order to fully understand this important part of eukaryotic biology, it would be desirable to have quantitative computer models available that can predict such effects exactly.

mathematical models

 

 

 

 

 

 

 


 

 

 

 

 

 


We are currently still a long way from being able to develop such models. While computational procedures and mathematical frameworks exist that would allow us to develop and handle such models, the main remaining problem is the availability of sufficiently accurate quantitative data from in vivo studies. We are currently developing experimental approaches with the aim of improving the generation of quantitative datasets, and are also starting initial modelling exercises that are mainly aimed at providing estimates of the general translational activity in the cell. These initial modelling approaches will also allow us to more easily identify gaps in the existing datasets that need addressing before accurate models of the process of translation termination can be generated.

 

Acknowledgements:

Funding from: Wellcome Trust

 

 

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Year 2

  • BI518 Molecular Biology and Genetics
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Enquiries: Phone: +44 (0)1227 823743

School of Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ

Last Updated: 31/01/2017