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Unusual RNA/DNA structures in health and disease

  • Full or part time
    Dr N Gromak
  • Application Deadline
    Friday, January 10, 2020
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

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 in health and disease remain largely unknown.
The main aim of this project is to identify R-loop-interacting proteins 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.

Funding Notes

4 Year DPhil Prize Studentships cover University fees, a tax free stipend of ~£17,009 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

1. M.Groh and N.Gromak. Out of balance: R-loops in human disease. PLoS Genetics 10(9) (2014).e1004630.
2. 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.
3. 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.
4. Groh M, Albulescu LO, Cristini A, Gromak N. Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration. J Mol Biol. 2016 Oct 19. 2836(16)30445-4.
5. 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.
6. Cristini A, Groh M, Kristiansen MS, Gromak N.RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage. Cell Rep. 2018 May 8;23(6):1891-1905.
7. Cristini A, Ricci G, Britton S, Salimbeni S, Huang SN, Marinello J, Calsou P, Pommier Y, Favre G, Capranico G, Gromak N*, Sordet O*. Dual Processing of R-Loops and Topoisomerase I Induces Transcription-Dependent DNA Double-Strand Breaks. Cell Rep. 2019 Sep 17;28(12):3167-3181.

How good is research at University of Oxford in Biological Sciences?

FTE Category A staff submitted: 223.80

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