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Homologous recombination: when, where and how does it act?

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

Project Description

Our genomic DNA is constantly challenged by numerous environmental stresses, such as radiation and genotoxic drugs, as well as those arising from normal processes of cell growth, including DNA replication and transcription. One of the key cellular processes involved in safeguard against these stresses is homologous recombination (HR), which provides a powerful mechanism to repair broken DNA faithfully and therefore to maintain genome stability. Furthermore, mounting evidence points toward an additional role of HR in the protection of stressed replication forks, hence the prevention of DNA breakages. However, HR may also alter genomic information if it is engaged by mistake, resulting in genome instability phenotypes closely linked to developmental disorders, immunodeficiency, premature aging and cancer. The aim of this D.Phil project is to investigate how HR is regulated at the right time and location.

The group investigates regulatory mechanisms of HR, which is essentially catalysed by the RAD51 recombinase, aided by BRCA2 (breast cancer 2) and PALB2 (partner and localiser of BRCA2) [1-6]. Our current research focus includes understanding: how are certain genomic loci, which are ‘difficult-to-replicate’ and prone to break, protected by HR factors? Are the mechanisms differentially regulated according to the cell cycle? And what is the impact of HR in cell division and differentiation? The project will tackle these long-standing questions using a newly established system in the group, which allows locus-specific induction of genotoxic stress at a defined phase of the cell cycle. The project will use multidisciplinary approach, including protein biochemistry, molecular biology, high-resolution imaging, mass spectrometry-based quantitative proteomics, genome-wide deep sequencing and/or iPSC-based myeloid differentiation system.

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. Bleuyard JY, Fournier M, Nakato R, Couturier AM, Katou Y, Ralf C, Hester S, Dominguez D, Rhodes D, Humphrey TC, Shirahige K, Esashi F. (2017) MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress. Proc Natl Acad Sci U S A. 114, 7671-7676
2. Yata K., Bleuyard J.Y., Nakato R., Ralf C., Katou Y., Schwab R.A., Niedzwiedz W., Shirahige K., Esashi F. (2014) BRCA2 coordinates the activities of cell-cycle kinases to promote genome stability. Cell Rep. 7, 1547-59
3. Yata, K, Lloyd, J., Maslen, S., Bleuyard, J.Y., Skehel, M., Smerdon, S. J., Esashi, F. (2012) Plk1 and CK2 act in concert to regulate Rad51 during DNA double strand break repair. Mol. Cell 45, 371-83
4. Bleuyard, J.Y., Buisson, R., Masson, J.Y., Esashi, F. (2012) ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates DNA repair. EMBO Rep. 13, 135-41
5. Esashi, F., Galkin V.E., Yu X., Egelman, E. West S.C., (2007). Stabilisation of RAD51 nucleoprotein filament by the C-terminal region of BRCA2. Nat Struc Mol Biol. 14, 468-474
6. Esashi, F., Christ, N., Gannon, J., Liu, Y., Hunt, T., Jasin, M., West S.C. (2005). CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature (Article), 434, 598-604

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

FTE Category A staff submitted: 223.80

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