Protein Degradation In Cellular Response to Ionising Radiation
Investigating the importance of protein turnover in the DNA Damage Response.
My group has been addressing some of the fundamental biological questions relevant for DNA replication and repair, genome stability, oncology, radiation biology and cancer therapy (Figure 1). The overarching goal of the Ramadan laboratory is to elucidate the role of the ubiquitin-chaperon p97/VCP (p97) in two basic biological processes: chromatin-associated protein degradation (CHROMAD) and DNA-protein crosslink (DPC) proteolysis in genome stability and cellular response to radio- and chemo-therapy. We use DNA double strand break repair and DNA replication as the model systems to address our questions. p97 is an AAA+ ATPase that together with its cofactors, associated E3-ubiquitin ligases and deubiquitinating enzymes forms the p97 system, which plays one of the central roles in the ubiquitin system and protein homeostasis. Thus, the p97 system contributes to both physiological (e.g., genome stability) and pathological processes such as cancer cell survival and progression.
Over the past decade the work of the Ramadan group (Figure 1) has directly demonstrated that p97-dependent protein disassembly and degradation on chromatin is essential for genome stability. However, it is not known how many different p97 complexes exist on chromatin, what is the composition of p97’s cofactors and substrates and how exactly different p97 complexes regulate DNA replication and DNA damage response after IR. By investigating the molecular mechanisms of the p97 system in DNA replication and DNA damage response after IR, this research programme aims to understand how protein turnover and degradation regulate genome stability, thus protecting cells from tumorigenesis and accelerated ageing. As the components of the p97 system emerge as druggable targets for cancer therapy and radiosensitisers, our ultimate goal is to identify a strong translational potential between our discoveries and cancer diagnosis and therapy. We are mostly using biochemical, cell and molecular biological approaches to address our questions.