We aim to understand how repair of damaged DNA is controlled during chromosome duplication, and why potentially dangerous changes in the behaviour of cells can occur when this process goes wrong.
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.
Peter McHugh is Professor of Molecular Oncology and Group Leader in the Department of Oncology. Following a period of post-doctoral research at University College London, he was awarded a Royal Society University Research Fellowship in 2001. In 2002 he joined the Oncology Laboratories at the MRC Weatherall Institute of Molecular Medicine, where he heads the DNA Damage and Repair research group. He is a regular presenter to Cancer Research UK fundraisers, and is a co-organiser of the UK Genome Stability Network Annual meeting and of the FEBS Nucleotide Excision Repair and Interstrand Crosslink repair meeting.
Broderick R, Nieminuszczy J, Baddock HT, Deshpande RA, Gileadi O, Paull TT, McHugh PJ, Niedzwiedz W. 2016. EXD2 promotes homologous recombination by facilitating DNA end resection. Nat Cell Biol, 18 (3), pp. 271-280.
Pettinati I, Brem J, Lee SY, McHugh PJ, Schofield CJ. 2016. The Chemical Biology of Human Metallo-β-Lactamase Fold Proteins. Trends Biochem Sci, 41 (4), pp. 338-355.
Lee SY, Brem J, Pettinati I, Claridge TD, Gileadi O, Schofield CJ, McHugh PJ. 2016. Cephalosporins inhibit human metallo β-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo. Chem Commun (Camb), 52 (40), pp. 6727-6730.
Allerston CK, Lee SY, Newman JA, Schofield CJ, McHugh PJ, Gileadi O. 2015. The structures of the SNM1A and SNM1B/Apollo nuclease domains reveal a potential basis for their distinct DNA processing activities. Nucleic Acids Res, 43 (22), pp. 11047-11060.
Brem J, van Berkel SS, Zollman D, Lee SY, Gileadi O, McHugh PJ, Walsh TR, McDonough MA, Schofield CJ. 2016. Structural Basis of Metallo-β-Lactamase Inhibition by Captopril Stereoisomers. Antimicrob Agents Chemother, 60 (1), pp. 142-150.
Iyama T, Lee SY, Berquist BR, Gileadi O, Bohr VA, Seidman MM, McHugh PJ, Wilson DM. 2015. CSB interacts with SNM1A and promotes DNA interstrand crosslink processing. Nucleic Acids Res, 43 (1), pp. 247-258.
Hatch SB, Swift LP, Caporali S, Carter R, Hill EJ, Macgregor TP, D'Atri S, Middleton MR, McHugh PJ, Sharma RA. 2014. XPF protein levels determine sensitivity of malignant melanoma cells to oxaliplatin chemotherapy: Suitability as a biomarker for patient selection International Journal of Cancer, 134 (6), pp. 1495-1503.
Srivas R, Costelloe T, Carvunis AR, Sarkar S, Malta E, Sun SM, Pool M, Licon K, van Welsem T, van Leeuwen F, McHugh PJ, van Attikum H, Ideker T et al. 2013. A UV-induced genetic network links the RSC complex to nucleotide excision repair and shows dose-dependent rewiring. Cell Rep, 5 (6), pp. 1714-1724. Read abstract | Read more
Ward TA, Dudášová Z, Sarkar S, Bhide MR, Vlasáková D, Chovanec M, McHugh PJ. Components of a Fanconi-like pathway control Pso2-independent DNA interstrand crosslink repair in yeast. PLoS Genet. 2012;8: e1002884
Wang AT, Sengerová B, Cattell E, Inagawa T, Hartley JM, Kiakos K, Burgess-Brown N, Enzlin JH, Schofield CJ, Gileadi O, Hartley JA, McHugh PJ. Human SNM1A and XPF-ERCC1 collaborate to initiate DNA interstrand cross-link repair. Genes and Development 2011; 25 (17):1859-70.
Sarkar S, Kiely R, McHugh PJ. The Ino80 chromatin-remodeling complex restores chromatin structure during UV DNA damage repair. J. Cell Biol. 2010; 13;191(6):1061-8.