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Peter McHugh

The DNA contained in our chromosomes holds our genetic blueprint (genome). Before dividing, cells must copy their DNA accurately to prevent changes being introduced into our genome. DNA damage can lead to errors being created during chromosome replication, including mutations that lead to cancer. Cells have evolved elaborate repair mechanisms to fix this damage and ensure that the genetic information is faithfully duplicated. Understanding these mechanisms has important implications for efforts to prevent cancer, while also helping identify individuals who might be at increased risk of developing cancer.

A related aspect of our work focuses on improving cancer treatment. Many chemotherapy drugs and radiotherapy kill tumour cells by damaging their chromosomal DNA. For many cancer patients, such treatment improves their chances of survival, but sometimes these approaches fail. There is evidence that an increased capacity to repair the DNA damage induced by cancer therapies is an important factor in treatment failure.

One area of particular interest is the repair of DNA inter-strand 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.  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.

Related to these ICL repair studies, we have a major interest in a family of DNA repair factors that contain a metallo-β-lactamase fold. These factors, the human SNM1 (DCLRE1)-family nucleases, play a key role in processing of ICLs and other forms of DNA damage.  Here, 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.

 

 

 

 

 

Figure 1: The domain organsiation of the three metallo-β-lactamase fold DNA repair enzymes found in humans. The MBL fold is shown in blue and the distal β-CASP (CPSF-Artemis-SNM1-Pso2) domain is shown in green. Highly conserved motifs within these are highlighted.

Figure 2: How does SNM1A initiate interstrand crosslink repair? Our work suggests that the SNM1A nuclease (in green) can bind DNA at a single nick and digest past the ICL, removing one of the damaged strands. This will permit downstream processes such as homologous recombination and damage tolerance mechanisms to effect complete repair of the ICL.

Selected Publications

Related research themes