Research Seminar: DNA repair nucleases – mechanism and inhibition

Professor Peter McHugh, Department of Oncology, University of Oxford

Tuesday 13th March, 1.00 p.m., Stacey Lecture Theatre 1

Every time a cell divides, it must copy its DNA with near-perfect accuracy to prevent changes being introduced into our genome. Any damage to DNA can create errors during this replication process, including the mutations that can lead to cancer.  Our work on DNA damage and repair mechanism also underpins our work on improving cancer treatment. Many chemotherapy drugs and radiotherapy treatments kill tumour cells by damaging their chromosomal DNA. These treatments sometimes fail and there is evidence that an increased capacity to tolerate or repair the DNA damage induced by cancer therapies is an important factor in treatment failure. We aim to understand why treatment sometimes fails, and use this information to develop novel strategies for treating cancer.

One area of particular interest is the repair of DNA interstrand crosslinks (ICLs), which are formed when the two strands of the DNA double-helix become covalently linked together. ICLs are an extremely toxic form of DNA damage that prevent fundamental processes including DNA replication and transcription. Defects in ICL repair result in cancer pre-disposition syndromes, such as Fanconi anemia, underlining the importance of ICL repair in human development and cancer avoidance. We are using a combination of cell biology, genetic, biochemical and structural approaches to reveal how repair complexes are delivered to sites of ICL damage during DNA replication, and to characterise the reactions they undertake to initiate DNA repair. Our basic research programme is coupled to collaborations with chemists and structural biologists with the aim of developing inhibitors of repair factors, to help overcome tumour resistance to DNA damaging chemotherapy and radiotherapy.