The Genome Damage and Stability Centre offers 3.5 year MRC-funded studentships in the following research areas:
- Cancer research
- Human genetic disease
- DNA repair mechanisms
- Cell cycle control
- Cell division
- Chromatin organisation
- Telomere Biology
The following 3.5-year PhD positions are available from September 2013:
Matt Neale’s laboratory
Project: Investigating DNA repair reactions on intact chromatin substrates
For cells and organisms to survive and propagate, they must accurately pass on their genetic information to the next generation. Errors in this process may arise from spontaneous mistakes in normal cellular metabolism, or from exposure to external agents such as chemical mutagens and radiation. To protect themselves from the consequences of DNA damage, cells have evolved an array of DNA repair pathways, each optimised for the resolution of a particular problem. One method of DNA repair, called homologous recombination (HR), involves using intact undamaged DNA sequences as a template to repair the damaged copy. HR is used extensively in meiotic cells to repair DNA breaks that are purposely created by the cell. In this context, HR is not just a repair mechanism, but also a method to drive interaction and genetic exchange between maternally and paternally inherited chromosomes, creating haploid genomes that are chimeras of the parental genetic information. Thus, the study of DNA repair and recombination informs our understanding of mechanisms that maintain genome stability, but which also generate genetic diversity, topics that are as critical to the survival of an individual cell as they are for the evolution and survival of an entire ecosystem.
The PhD project offered will involve the genetic and biochemical investigation of the meiotic DNA repair pathway using the simple eukaryotic budding yeast, Saccharomyces cerevisiae as a model system. The project will use advanced molecular biology, genetic, and biochemical methods to regulate and analyse protein-DNA reactions, and will suit an accomplished candidate interested in deciphering molecular mechanism. From these studies we hope to gain a much clearer picture of how cells respond to and repair DNA damage in the context of the complex chromosomal structure, and how such repair reactions create the genetic rearrangements necessary for productive meiotic nuclear division.
For further information about this project, please contact: Matt Neale firstname.lastname@example.org
This studentship will funded by the Europen Research Council (ERC) and available to start September 2013. Applications from UK/EU students only.
For background of the Neale lab research, please consult some of our recent publications:
Garcia, V., Phelps, S. P., Gray, S. and M. J. Neale (2011). Bidirectional resection of DNA double-strand breaks by Mre11 and Exo1. Nature 144(5): 719-31.
Pan, J., M. Sasaki, R. Kniewel, H. Murakami, H. G. Blitzblau, S. E. Tischfield, X. Zhu, M. J. Neale, M. Jasin, N. D. Socci, A. Hochwagen, and S. Keeney (2011). A Hierarchical Combination of Factors Shapes the Genome-wide Topography of Yeast Meiotic Recombination Initiation. Cell 144(5): 719-31.
Neale, M. J. (2010). PRDM9 points the zinc finger at meiotic recombination hotspots. Genome Biology 11: 104.
Dr Aidan Doherty's laboratory
Project: DNA Damage Tolerance and Genome Replication in Human Cells
DNA damage tolerance pathways allow our cells to bypass lesions that would otherwise block DNA replication, enabling them to survive major genotoxic stress and maintain genomic integrity. Lesion bypass DNA polymerases play a central role in the cellular mechanisms that facilitate damage tolerance and mutations in these replicative enzymes are associated with ageing and major human diseases, including cancer. The aim of this project is to study the molecular mechanisms of cellular pathways that promote efficient genome replication at sites of DNA damage. This multi-disciplinary project will integrate state of the art cellular, genetic and biochemical approaches to identify and characterise novel polymerase-mediated pathways that facilitate damage tolerance during chromosomal replication in human cells. The successful applicant will join the Genome Damage and Stability Centre, an internationally renowned Institute carrying out research on the response of cells to DNA damage, genome instability and its relationship to human disease. We provide a stimulating and supportive research environment and our expertise covers a wide range of experimental systems. Further information about our research can be obtained from our website at http://www.sussex.ac.uk/gdsc/ .
Funding Notes:Applicants should hold qualifications at the level of, or equivalent to, a first or upper second class honours degree in biochemistry, cell biology or a related subject. Formal applications should be made using our online application system at http://www.sussex.ac.uk/study/pg/applying/ Include a full CV, two references, transcripts and statement of interest. Project enquiries should be sent to Prof. Aidan Doherty (AJD21@sussex.ac.uk) Application enquiries should be sent to Dr Deeptima Massey (email@example.com).
References:Loeb, L. A., & Monnat, R. J. (2008) DNA polymerases and human disease. Nature Reviews Genetics, 9, 594–604. Sale, J. E., Lehmann, A. R., & Woodgate, R. (2012) Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nature Reviews Molecular Cell Biology, 13, 141–152.
Dr Mark O'Driscoll's laboratory
Project: Impairments of the DNA Damage Response underlying human developmental disease.
Defects in the DNA damage response and repair machinery that ensures optimal genome stability are associated with complex phenotypes including cancer. It is now clear that some of these defects also have profound impacts upon normal human development, particularly regarding neurogenesis, skeletal development and organismal growth. This is illustrated by the association of impaired ATR-pathway function with various syndromes falling under the umbrella of Microcephalic Primordial Dwarfisms (e.g. Seckel syndrome, Microcephalic Osteodyspalstic Primordial Dwarfism type II). How defects in the DNA damage response cause these developmental abnormalities is unclear. Using patient-derived cell lines from several novel human developmental disorders as a research tool, the aim of this project is to construct at patho-mechanistic link between genotype and phenotype to help explain this complex outcome of impaired genome stability.
Directly funded for UK/European students only.
(related to your research topic).
O’Driscoll M.Cold Spring Harb Perspect Biol. 2012 Dec 1;4(12). doi:pii: a012773.
Diseases associated with defective responses to DNA damage.
Ogi T et al. PLoS Genetics, 2012. Nov: 8(11):e1002945
Identification of the first ATRIP-Deficient patient and novel mutations in ATR define a clinical spectrum for ATR-STRIP Seckel syndrome.
Rivière JB et al. Nature Genetics, 2012. Jun 24;44(8):934-40.
De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.
Kerzendorfer C et al. Hum Mol Genet 2012 May 15;21(10):2181-93.
Characterising the functional consequences of haploinsufficiency of NELF-A (WHSC2) and SLBP identifies novel cellular phenotypes in Wolf-Hirshhorn syndrome.
Outwin E et al. PLOS Genetics. 2011 Aug;7(8):e1002247.
Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome.
Bicknell LS et al. Nat Genet. 2011 Feb 27;43(4):350-5.
Kerzendorfer C & O’Driscoll M. DNA Repair 2009 Sept 2; 8(9): 1139-1152.
Human DNA damage response & repair deficiency syndromes: linking genomic instability and cell cycle checkpoint proficiency.
For further details of our current vacancies mentioned on the home page please click on: http://www.sussex.ac.uk/aboutus/jobs