Nucleotide-excision repair (NER) is a biological mechanism for repairing DNA damage in all living organisms, including human. This very complex process involves co-operation of more than 30 different proteins bound to a DNA damage site and maintains the integrity of our genome. Unfortunately, to date, NER and its components are not fully understood. DNA damage occurs spontaneously on the daily basis in our organisms but its’ occurrence increases significantly after exposure to car exhaust, cigarette smoke and other environmental toxins as well as UV radiation from sunlight. Genetic defects in NER are associated with a range of disorders characterized by high incidence of skin cancer and in severe cases neurological and developmental disease. NER is also critical for the development of resistance to antitumor drugs such as cisplatin that function by damaging DNA. NER is, therefore, a potential target for developing more effective anticancer combination therapies.

My project in the Chazin Laboratory is addressed to the understanding of the role of XPA and RPA proteins in damaged DNA repair process. It is already known that XPA protein works a scaffold for the multi-protein complex assembly in the latter steps of DNA repair, following DNA damage recognition. XPA works in conjunction with replication protein A (RPA) but details of their interaction, as well as their positioning on the NER bubble, remain unclear. Moreover, malfunction of XPA protein was found to cause the most severe symptoms of Xeroderma Pigmentosum disease. In XP disease, the ability to repair damage caused by ultraviolet (UV) light is deficient. Multiple basal cell carcinomas (basaliomas) and other skin malignancies frequently occur at a young age in those with XP, and metastatic malignant melanoma and squamous cell carcinoma are the two most common causes of death in XP victims.

My goal is to define the structural and molecular details of XPA-RPA interaction using a combination of structural biology techniques, including NMR, crystallography, electron microscopy and SAXS with molecular biology tools such as confocal microscopy on patient-derived cell lines. Eventually, the analysis will be extended to other proteins, accompanying XPA and RPA in the assembly of very complex NER machinery. This project is a part of the Structural Cell Biology of DNA Repair Machines (SBDR) consortium, a multi-institutional Program, which addresses the challenge of understanding at the molecular level the pathways controlling genetic integrity. I am open to new ideas and collaboration opportunities.