2 PhD studentships

/ C. elegans / apoptosis / genome stability /Gartner lab / Dundee / UK

My laboratory uses the nematode worm C. elegans as a model system to understand basic biological questions and we mainly focus on the mechanisms that are required to maintain genome stability. We currently have two PhD positions available and are looking for outstanding candidates. Candidates should ideally already have been exposed to a laboratory environment. While previous experience in C. elegans is not necessary, this, or experience with a genetic system would certainly be a plus but is not necessary. An outline of two potential projects is given below.

In response to distortions of the double helix or upon exposure to certain genotoxic stress such as Hydroxyurea (HU) treatment, cell respond by activating the replication checkpoint to stabilize stalled replication forks, to inhibit late origin firing and to delay cell cycle progression. These mechanisms are important for cancerogenesis and tumour therapy. We plan to analyse the S-phase checkpoint using C. elegans as model. We will (aim 1) perform genetic mapping and complementation with worm mutants resistant to HU treatment to focus on the positional cloning of one or two novel genes affecting the S-phase checkpoint. To pinpoint their mechanism of action (aim 2) we will genetically determine their epistatic relationship by double and triple mutant analysis and we will use immuno-cytological assays including cell cycle specifically expressed- or localized proteins, cytological markers indicative of double strand breaks and the cytological monitoring of DNA synthesis by BRDU staining for further characterization. Finally (aim 3), we will try to translate our findings into vertebrate tissue culture and or Xenopus extract systems.

DNA damage checkpoint pathways are needed to detect DNA damage and transduce a signal that elicits cell cycle arrest, DNA repair, and/or programmed cell death. Defects in DNA damage checkpoint signalling, have a dramatic impact on genome stability and are implicated in tumorogenesis, as well as in some genetic instability disorders like, for instance, Li-Fraumeni syndrome and Ataxia Telangiectasia. Previously we defined a core pathway needed for DNA damage induced apoptosis that includes conserved upstream checkpoint genes, needed for sensing of DNA damage as well as the C. elegans homolog of p53 termed cep-1 which is specifically needed for DNA damage induced apoptosis. To further define components of DNA damage signalling we screened through a collection of radiation sensitive mutants provided by the Ahmed lab and found mutants specifically defective in DNA damage induced apoptosis that fall into two classes. The first class is likely to act in the cep-1/p53 pathway and is defective in the cep-1 dependent induction of egl-1 while the second class seems to affect a pathway parallel to cep-1/p53 as DNA damage induced egl-1 transcription is normal. We propose to follow up on one of these mutants and to positionally clone the corresponding gene. This novel apoptosis gene will be placed into the genetic pathways by double and triple mutant analysis. Furthermore, it will also be attempted to understand the molecular mechanism of this novel apoptosis gene and to asses weather it is evolutionarily conserved.

To attract the very best candidates those 4 years studentships will be topped to the Dundee price studentship level which is (tax free) £15 000 /year.

For further information about our projects, our department, the University of Dundee or about living in Scotland please look at my website. Please do not hesitate to send me informal enquiries.

a.gartner@dundee.ac.uk
http://www.dundee.ac.uk/lifesciences/gartner/index.htm

A. Woodward , T. Göhler , M. Gloria Luciani , M Oehlmann, X. Ge, A. Gartner, D. Jackson and J. Blow (2006) Excess Mcm2-7 license dormant origins of replication for use when replication fork progress is inhibited, J Cell Biol. 2006 173(5):673-83.

B. Meier, I. Clejab, Y. Liu, M, Lowden, A. Gartner, J. Hodgkin and S. Ahmed (2006). trt-1 Is the Caenorhabditis elegans Catalytic Subunit of Telomerase. PLoS Genet. 2006 Feb 10;2(2)

B. Schumacher, M. Hanazawa, MH. Lee, S. Nayak, K. Volkmann; R. Hofmann, M. Hengartner, T. Schedl and A. Gartner (2005).Translational Repression of C. elegans p53 by GLD-1 regulates DNA damage induced apoptosis. Cell 120: 357-368

B. Schumacher, C. Schertel, N.Wittenburg, S. Tuck, S. Mitani, A. Gartner *, B. Conradt and SC. Shaham. (2005). C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. Cell Death Differ. 2005 12(2):153-61 Co-corresponding author