We are interested in the role of the ubiquitin-proteasome system in DNA repair, ageing, cancer and radiotherapy.
The research focus of the group is to understand the role of the ubiquitin-proteasome system (UPS) and its central component p97/VCP in genome stability. We aim to understand how can we use this knowledge to improve current cancer therapy, especially after ionizing radiation. p97/VCP is a evolutionarily conserved segregase that with the help of specific cofactors binds and remodels (segregates) diverse and mostly ubiquitinated proteins (substrates) in a variety of cellular processes and compartments. In this way p97/VCP and its cofactors play an essential role in the maintenance of protein balance (homeostasis) in the cell. We are especially interested in chromatin-related p97/VCP functions and consequently in chromatin-related protein homeostasis (Figure 1; p97/VCP-dependent chromatin-associated protein homeostasis) after DNA damage. Chromatin is the substance of a cell nucleus consisting of DNA, RNA and proteins, and the basic source of genetic information.
Using biochemical and cell biological approaches we are investigating fundamental molecular aspects of protein homeostasis in DNA replication, DNA repair and DNA damage response. Mechanistic insights of basic cellular processes related to DNA metabolism and related protein homeostasis can improve our knowledge of ageing and ageing related diseases as well as current diagnosis, prognosis and treatment of cancer.
We have identified the essential role of p97/VCP in chromatin and in DNA damage response, after ionizing and ultraviolet radiation. We have discovered a new human syndrome characterised by premature-ageing and early-onset hepatocellular carcinoma (Figure 2; green arrow indicates tumour mass) that is caused by mutations in p97-cofactor SPRTN (Figure 3; genomic localisation and protein structure of SPRTN with patient mutations).
Our results strongly suggest that protein-induced chromatin stress (PICROS; pathological accumulation of proteins on chromatin) plays an essential role in cancer and ageing. The group is currently trying to understand how chromatin-associated protein homeostasis regulates PICROS and thus prevents accelerated ageing and cancer. We believe that understanding of PICROS might open new avenues in cancer diagnosis, prognosis and therapy, but also answer fundamental questions about ageing.
Kristijan Ramadan is a Senior Group Leader and Associate Professor at the CRUK/MRC Oxford Institute for Radiation Oncology. He holds degrees in Veterinary Medicine (DVM) and Pathology (MSc), and a PhD in Biochemistry and Molecular Biology. Between 2009 and 2013 he was a Junior Group Leader and Lecturer at the Institute of Pharmacology and Toxicology-Vetsuisse, University of Zurich. He received a 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 due to mutations in SPRTN gene.
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: 866-878
Vaz et al. DNA-protein crosslink proteolysis repair. Trends in Biochemical Sciences, 2017. Jun: 42: 483-495. DOI: 10.1016/j.tibs.2017.03.005
Vaz et al. Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair. Molecular Cell, 2016, Nov 17, 64: 1-16
Ramadan K et al. Strategic role of the ubiquitin-dependent molecular segregase p97 (VCP/Cdc48) in DNA replication. Chromosoma, 2016, Apr 14, DOI:10.1007/s00412-016-0587-4
Lessel et al. Mutations in SPRTN cause early-onset hepatocellular carcinoma, genomic instability and progeriod features. Nature Genetics, 2014 Nov;46 (11):1239-44.
Puumalainen at al. Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity. Nature Communications, 2014 Apr 28;5:3695.
Meerang at al. The ubiquitin selective remodelling factor p97/VCP orchestrates the DNA damage response. Nature Cell Biology, 2011 Oct 23;13(11):1376-82.
Ramadan at al. Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin. Nature, 2007 Dec 20;450(7173):1258-62.