McHugh Group: DNA Damage and Repair

The DNA in our chromosomes holds our genetic blueprint or genome. 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. Cells have evolved elaborate repair mechanisms to fix this damage and ensure that the genetic information is faithfully reproduced. Our focus is on understanding these repair mechanisms at the molecular level. This has important implications for our efforts to prevent cancer, while also helping identify individuals who might be at increased risk of developing 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. For many cancer patients, these treatments improve their chances of survival, but for some these approaches fail. 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.

XPF-ERCC1 endonuclease initiates ICL repair in collaboration with RPA and the MBL-fold nuclease SNM1A

One area of major 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 cellular 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. Conversely, many important cancer chemotherapeutics work through ICL formation. Together, these facts emphasise the importance of understanding ICL repair for improving cancer prevention and treatment strategies. Here, we are focussed on understanding the nucleases and associated proteins that act to incise the DNA during ICL repair, with a focus on the XPF^FANCQ-ERCC1 endonuclease, and the associated SLX4^FANCP factor. We are using a combination of cell biology, genetic, biochemical and structural approaches to reveal how these nuclease complexes are delivered to sites of DNA damage during DNA replication, and to characterise the reactions they undertake to initiate DNA repair at the replication fork.

Related to these ICL repair studies, we also have major interest is in another family of DNA repair nuclease; those that contain a metallo-β-lactamase (MBL) fold. The MBL factors, including the human SNM1 (DCLRE1)-family nucleases, play a key role in processing of ICLs as well as other forms of DNA damage including the DNA double-strand breaks induced by radiation. Here, our basic research programme using biochemistry, genetics and cell biology 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.