POST-TRANSLATIONAL MODIFICATIONS IN CELLULAR RESPONSE TO IONIZING RADIATION

Lead: Prof Dr Kristijan Ramadan 

The Ramadan laboratory aims to understand the basic mechanisms of post-translational modifications, primarily ubiquitination and SUMOylation in the maintenance of genome stability. We are especially focused on mechanistic insight into the role of the ubiquitin system and protein degradation in DNA replication, DNA double strand break repair and DNA-protein crosslink repair. This knowledge helps us to design better modalities of cancer therapy. We have a possibility to hire a DPhil/PhD student who would like to explore the role of the ubiquitin system and DNA-protein crosslink repair in response to ionizing radiation, one of the major modalities to treat cancer. You will be using standard molecular, biochemical and cell biological techniques coupled to the state-of-the-art technologies such as CRISPR/Cas9 gene editing, mass-spectrometry and super-resolution microscopy. Your work will elucidate the mechanisms of cancer cell response to ionizing radiation and identify potential druggable targets that could improve radiotherapy in cancer treatment.

If you are interested in this post please apply to: https://www.oncology.ox.ac.uk/study-with-us/dphil-phd-programme/how-to-apply

Applications for October 2021 entry are now open. The deadline for applications is midday Friday 8 January 2021. 

If you want to know more about the project, please contact me via e-mail:

kristijan.ramadan@oncology.ox.ac.uk

Selected References:

Fielden et al. TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nature Commun. 2020, Mar 9;11(1):1274. doi: 10.1038/s41467-020-15000-w.

Singh et al.  Homeostasis of the E3-ubiquitin ligase RNF8 by the p97-Ataxin 3 complex preserves genome stability. EMBO J, 2019 Oct 4;38(21):e102361. doi: 10.15252/embj.2019102361.

Halder et al. SPRTN protease and CHK1 kinase Cross-Activation loop Safeguards DNA replication. Nature Commun. 2019, 10; 3142 https://doi.org/10.1038/s41467-019-11095-y.

Baranes-Bachar K et al. The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair. Molecular Cell. 2018 Mar 1;69(5):866-878.e7. doi: 10.1016/j.molcel.2018.02.002.

Vaz B et al. Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair. Molecular Cell. 2016 Nov 17;64(4):704-719. doi: 10.1016/j.molcel.2016.09.032

Lessel D et al. Mutations in DVC1/SPRTN cause a syndrome with early-onset hepatocellular carcinoma, genomic instability and progeroid features. Nature Genetics. 2014 Nov;46(11):1239-44. doi: 10.1038/ng.3103. 

Puumalainen MR et al. Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity. Nature Commun. 2014 Apr 28;5:3695. doi: 10.1038/ncomms4695.

Meerang M et al. The ubiquitin selective remodelling factor p97/VCP orchestrates the DNA damage response. Nature Cell Biol. 2011 Oct 23;13(11):1376-82. doi: 10.1038/ncb2367.

Ramadan K et al. Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin. Nature. 2007 Dec 20;450(7173):1258-62

We are interested in the role of proteolysis and p97/VCP/Cdc48 system in DNA replication, DNA repair, ageing, cancer and radiotherapy.

We use biochemical, cell and molecular biology approaches to study basic cellular processes for the maintenance of genome stability. We believe that our research not only contributes to deeper understanding of the fundamental biological processes but also paves the path for novel therapeutic interventions in various malignancies.    

Kristijan holds degrees in Veterinary Medicine (DVM), Veterinary Pathology (MSc) and PhD in Biochemistry and Molecular Biology under supervision of Prof. Dr. U. Hübscher. He did his post-doctoral training at the ETH-Zürich in the group of Dr H. Meyer. Between 2009 and 2013 he was Junior Group Leader and Lecturer at the Institute of Pharmacology and Toxicology-Vetsuisse, University of Zürich. In 2013 he moved to the UK to join the Oxford Institute for Radiation Oncology at the Department of Oncology as MRC Senior Group leader. From 2014 to 2019 he was Associate Professor at the Department of Oncology, University of Oxford. In 2019 Kristijan was promoted to the Full Professor of Molecular Medicine at University of Oxford.

Kristijan received the Proud of Croatia Award (Croatian Hero for 2014) for his scientific contribution in saving the life of a young boy who suffered from liver cancer caused by mutations in the SPRTN gene.

His work contributed to the discoveries of Chromatin-Associated Degradation, DNA-protein crosslink proteolysis repair and Ruijs-Aalfs Syndrome (RJALS). 

In 2020 Kristijan was elected to the Croatian Academy of Sciences and Arts (HAZU) as a distinguished scientist in the field of Medicine.

Students:

Ftoon Aljarbou, DPhil Student

Gwendoline Hoslett, DPhil Student

Pauline Lascaux, DPhil Student

Cristiano Peron, MD, DPhil Student

Stelios (Alex) Koukouravas,  MRes Student

Juntong Xu, MRes student

Post-doctoral Researchers:

Dr. Annamaria Ruggiano

Dr. Abhay Narayan Singh

Dr. Ignacio Torrecilia

Dr. Wei Song

1. Matthias Bosshard (2009-2010); MSc and Doctor Vet Med Student 2009-2010; shared with Prof Hübscher University of Zurich) - next destination: PhD/DPhil Student, University of Zurich, Switzerland

2. Dr Mayura Meerang (2009-2011) Postdoctoral Researcher - next destination: Postdoctoral Researcher, University Hospital Zurich, Switzerland

3. Sebastian Koller (2011-2013) MSc and Doctor Vet Med Student - next destination: City Delegate/Politician, Region Wil, Switzerland

4. Divya Achuthankutty  (2014-2015) MSc Student - next destination: PhD student, University of Copenhagen, Denmark

5. Domenic Pilger (2015) MSc Student (shared with Prof T. Hoppe, University of Cologne) – next destination: PhD student, Gurdon Institute, University of Cambridge, UK

6. Henry Bickers (2016) MSc Student - Ministry of Defence, UK

7. Dr. Swagata Halder (2012-2016) DPhil Student and Postdoctoral Researcher (2017) - next destination: Postdoctoral Researcher, International Institute for Molecular Oncology, Milan, Italy.

8. Dr. Judith Oehler (2012-2016) DPhil Student and Postdoctoral Researcher (2017) - next destination: Postdoctoral Researcher, Department of Biochemistry, University of Oxford, UK

9. Katherine Wiseman (2013-2017) DPhil Student - next destination: Scientist, Immunocore Ltd, Oxford, UK

10. Dr Marta Popovic (2014-2017) Postdoctoral Researcher - next destination: Junior Group Leader/Assistant Professor at Institute Rudjer Boskovic, Zagreb, Croatia

11. Giyun (Laura) Yoo (2017) MSc Student - next destination: PhD Student, Imperial College London, UK

12. Mirjam Kümmerlin (2018) MRes Student - next destination: Postgraduate Study in Chemistry at Ludwig Maximilian University, Munich, Germany

13. Anouk Sesink (2019) MRes Student - next destination: PhD student at the Curie Institute, Paris, France

14. Dr Bruno Vaz (2012-2019) Postdoctoral Researcher - next destination: Scientist, SENTCELL, Rome, Italy

15. Dr John Fielden (2015-2020) DPhil Student (2015-2019) and Postdoctoral Researcher (2020) - next destination: Institute of Molecular Health Sciences, Swiss Federal Institute of Technology-Zurich (ETH), Switzerland

16. Samuel Hume (2016-2020) DPhil student - next destination: Medical School Oxford, UK.

17. Susan Kilgas (MRes and DPhil student 2016-2022) - next destination: Postdoctoral researcher Dana-Farber Cancer Institute, Harvard Medical School, USA.

18. Shudong Li (DPhil student 2017-2022) - next destination: Postdoctoral researcher at The Francis Crick Institute-London, UK.

MRC RESEARCH PROGRAMME:

Protein Degradation In Cellular Response to Ionising Radiation