Graduate Student and Postdoctoral Positions: Enquiries with CV welcome.

Please e-mail Natalia Gromak directly with enquiries (natalia.gromak@path.ox.ac.uk)

Departmental Studentship competition 2018:

https://www.findaphd.com/search/ProjectDetails.aspx?PJID=89226

Deadline: Friday, March 09, 2018

Unusual RNA/DNA structures (R-loops) are formed when the RNA hybridizes to a complementary DNA strand, displacing the other DNA strand in this process. R-loops are detected in all living organisms and play crucial roles in regulating gene expression, DNA and histone modifications, generation of antibody diversity, DNA replication and genome stability. The work from the lab have recently demonstrated that R-loops are also implicated in human diseases, including neurodegeneration and cancer. Currently the molecular mechanisms associated with R-loop functions and proteins interacting with these structures remain largely unknown.

The main aim of this project is to identify R-loop-interacting proteins in unbiased way and characterise their functions in health and disease. We will employ state-of-the-art CRISPR, Mass Spectrometry and molecular biology approaches to build a protein network, R-loop interactome, involved in recognition and resolution of R-loops in human cells. The results generated in this project will help to uncover the molecular mechanisms underlying the pathology of Friedreich ataxia (FRDA) and Fragile X syndrome (FXS), trinucleotide expansion disorders associated with pathological R-loops. In the long term the findings from this project will be essential for the development of new therapeutic approaches for FRDA and FXS disorders.

References:

1.Groh M, Albulescu LO, Cristini A, Gromak N. Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration. J Mol Biol. 2016 Oct 19. pii: S0022-2836(16)30445-4.

2.Kotsantis P, Silva LM, Irmscher S, Jones RM, Folkes L, Gromak N*, Petermann E*. Increased global transcription activity as a mechanism of replication stress in cancer. Nature Commun. 2016 Oct 11;7:13087.

3.M.Groh and N.Gromak. Out of balance: R-loops in human disease. PLoS Genetics 10(9) (2014).e1004630.

4.Kumari, D., and Usdin, K. (2012). Is Friedreich ataxia an epigenetic disorder? Clin Epigenetics 4, 2.

5.Santoro, M.R., Bray, S.M., and Warren, S.T. (2011). Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol 7, 219-245.

6.Aguilera, A., and Garcia-Muse, T. (2012). R loops: from transcription byproducts to threats to genome stability. Mol Cell 46, 115-124.

7.M.Groh, M.Lufino, R.Wade-Martins, N.Gromak. R-loops formed over expanded repeats cause transcriptional silencing in Friedreich ataxia and Fragile X syndrome. PLoS Genetics 10 (5) (2014). e1004318.

8.Skourti-Stathaki, K., Proudfoot, N.J., and Gromak, N. (2011). Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 42, 794-805.

9.M.Groh, L.M.Silva and N.Gromak. Mechanisms of transcriptional dysregulation in repeat expansion disorders. Biochem Soc Trans. 2014 Aug;42(4):1123-8.