DNA Damage & 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. Moreover, cancers often develop with defects in their DNA repair system making them vulnerable to inactivation of alternative pathways they become dependent upon. We aim to exploit these tumour defects by working with chemists to develop new agents that target a variety of DNA repair enzymes.
We have made major contributions to the study of several DNA repair pathways, but in particular the mechanism of DNA interstrand crosslink (ICL) repair. ICLs occur when the two complementary DNA strands become covalently joined together. This damage is extremely toxic as it prevents essential cellular processes such as transcription and DNA replication. We have employed a combination of biochemistry, genetics, cell biology, and structural biology approaches to define and mechanistically characterise the pathways that control ICL repair. These include pathways that are defective in individuals with inherited disorders in DNA repair including Fanconi anaemia, and Cockayne Syndrome.
At the same time, working with chemists, we have made considerable progress towards identifying and developing small molecule inhibitors of the DNA repair pathways and their constituent enzymes. We hope these will be, ultimately, of benefit to cancer patients by enabling the development of new medicines.
Sanja Brolih, Postdoctoral Researcher
Abimael Cruz-Migoni, Postdoctoral Researcher
Jennifer Gurnett, Postdoctoral Researcher
Matthew Harris, DPhil Student (with Yang Shi and Chris Schofield)
Lucy Henderson, DPhil Student
Malitha Ratnaweera, DPhil Student
Rebecca Roddan, Postdoctoral researcher
Lonnie Swift, Postdoctoral Researcher
Ceren Yalaz, Post-Doctoral Researcher
Baddock HT, Brolih S, Yosaatmadja Y, Ratnaweera M, Bielinski M, Swift LP, Cruz-Migoni A, Fan H, Keown J, Walker AP, Morris GM, Grimes JG, Fodor E, Schofield CJ, Gileadi O and McHugh PJ. (2022) Characterisation of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification, Nucleic Acids Research , 50(3), pp. 1484-1500.
Yosaatmadja Y, Baddock HT, Newman JA, Bielinski M, Gavard AE, Mukhopadhyay SMM, Dannerfjord AA, Schofield CJ, McHugh PJ*, Gileadi O. (2021) Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition, Nucleic Acids Research, 49(16), pp. 9310-9326.
Baddock HT, Newman JA, Yosaatmadja Y, Bielinski M, Schofield CJ, Gileadi O, McHugh PJ. (2021) A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family, Nucleic Acids Research, 49(16), pp. 9294-9309.
Wu, X et al. (2021) Neuronal enhancers are hotspots for DNA single-strand repair, Nature, 593(7859), pp. 440-444.
van Wietmarschen N et al. (2020) Repeat expansions confer WRN dependence in microsatellite-unstable cancers, Nature, 586(7828), pp. 292-298.
Abdullah UB, McGouran JF, Brolih S, Ptchelkine D, El-Sagheer AH, Brown T, McHugh, PJ* (2017) RPA activates the XPF-ERCC1 endonuclease to initiate processing of DNA interstrand crosslinks, The EMBO Journal, 36(14), pp. 2047-2060.
Erdal E, Haider S, Rehwinkel J, Harris AL*, McHugh PJ*. (2017) A pro-survival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1, Genes & Development, 31(4), pp. 353-369.