About the Project
Age-related diseases, particularly the increasing cancer rates, represent major challenge for health care systems. However, genes and molecular mechanisms essential for cancer and ageing are poorly understood. To successfully combat cancer and turn it into a chronic rather than life-treating disease, we have to understand molecular insight of cellular processes that are re-programming healthy cells to become cancer cells. Thanks to technology (e.g. whole genome sequencing), our understanding of cancer and ageing has tremendously increased in the last 15 years.
Past achievements and future goals of my research group are directly contributing to this aim. We have just discovered that monogenic and biallelic mutations in SPRTN gene cause hepatocellular carcinoma (HCC). This discovery is published in the most prestigious journal for human genetics (Nature Genetics) and is the first example of how monogenic mutations cause HCC. Interestingly, in addition to cancer, patients harbouring germline and biallelic mutations in SPRTN gene also developed symptoms of accelerating ageing, such as premature greying of hair, muscle and lipid dystrophy, decreased bone development or cataract. We have also proved that DNA damage and consequently genome instability is the cause of this novel human syndrome (“SPRTN-syndrome”). Now, we want to understand how do monogenic mutations in SPRTN cause genome instability and consequently cancer and ageing.
Your aim as a DPhil student will be to understand the molecular details of SPRTN protein function and to elucidate why SPRTN-mutations cause only liver cancer, but ageing related changes in other tissues? What are the cellular mechanisms that decide whether cells will go into uncontrolled proliferation (cancer) or will stop to proliferate (senescence-again)? How does SPRTN regulate these two, at the first glance completely opposite, processes? You will be using in vitro cell-biological and biochemical systems investigating these fundamental scientific questions in patient cell lines. Project will be also including characterization of SPRTN-syndrome mouse model.
References
Lessel D#, Vaz B#, Halder H#, Lockhart P.J#, Marinovic-Terzic I# at al. and, Terzic J*, Amor D.J*, Dikic I*, Ramadan K*, Kubisch Ch*. Mutations in SPRTN cause a syndrome with early-onset hepatocellular carcinoma, genomic instability and progeroid features. Nature Genetics 2014, Sept 28, advance online publication. (#these authors equally contributed to this discovery; *corresponding authors)
Puumalainen M.R, Lessel D, Ruthemann P, Kaczmarek N, Bachmann K, Ramadan K*, Hanspeter Naegeli*. Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity. Nature Commun. 2014 Apr 28;5:3695. (*corresponding authors)
Meerang M, Ritz D, Paliwal S, et al. and Ramadan K*. The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks. Nature Cell Biol 2011;13:1376-82. (*corresponding author)
Ramadan K, Bruderer R, Spiga FM, et al. Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin. Nature 2007;450:1258-62.