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DNA Damage and Repair: Studying DNA damage and repair to understand the causes of cancer and improve its treatment


Project Description

Our DNA is constantly under threat from damaging agents. If unrepaired this DNA damage can lead to errors during genome duplication, including the mutations that can lead to cancer and other human diseases. Cells have evolved elaborate repair mechanisms to fix this damage and ensure that the genetic information is faithfully reproduced and the McHugh group is dedicated to understanding these repair mechanisms at the molecular level. Equally importantly, DNA damage is induced during cancer therapy, and therefore our work is revealing new strategies for preventing and treating human disease, especially cancer.

We ultimately aim for a complete molecular and cellular understanding of critical DNA repair pathways that act on DNA damage. Our strategy is three-fold. First, our basic research programme aims to identify the factors involved in DNA repair, and to fully elucidate the molecular mechanism of these processes. We use a powerful combination of genetics, cell biology and biochemistry. Second, using cutting-edge structural biology platforms including x-ray crystallography and cryo-electron microscopy, we are elucidating the structures of the repair factors and also the large complexes they form within cells that are the functional units of DNA repair. Third, we are intensively applying chemical-biology studies to identify inhibitors of key enzymes involved in replication-associated DNA repair, since interfering with these factors might have potent antitumour effects. By virtue of the broad range of approached, we welcome applications from students from a wide variety of backgrounds, including chemists, biochemists, geneticists, structural biologists and clinicians.

Areas of of major interest include the interplay between DNA damage response and the interferon response. In collaboration with Jan Rehwinkel and Adrian Harris (MRC-WIMM), we described the accumulation of small cytoplasmic DNA fragments in cancer cells after therapeutic DNA damage, including radiotherapy and chemotherapy (Erdal et al, Genes & Dev. 2017). This induced the expression of a set of interferon (IFN)-stimulated genes comprising the ‘IFN-related DNA damage resistance signature’ (IRDS). The IRDS strongly correlates with resistance to cancer therapy and a worse patient outcome. While classically, during viral infection, the presence of foreign (viral) DNA in the cytoplasm of host cells initiates type-I IFN production as part of the innate immune system, how ‘self’ DNA is released from the nucleus of cancer cells during therapy to induce IFN signalling remains unknown. Employing deep sequencing and cutting-edge bioinformatic approaches, we are revealing the identity of these DNA fragments. Using ultra-resolution microscopy, genetics/genome editing techniques and biochemistry, we are discovering how the DNA fragments are produced. In the long-term we will determine how this ‘self’ DNA engages with the innate immune sensors including the key sensor, cGAS-STING, and analyse induction of the IFN response in clinical cancer samples. This will reveal new targets for future therapeutic intervention, and integrate with small molecule inhibitor discovery programmes to target DNA processing enzymes that are underway in our laboratories

Another major current focus is the structure and function of the SLX4 repair complex. The SLX4 nuclease platform plays a critical role in spatially targeting and modulating the activity of several structure-selective nucleases during replication fork repair and homologous recombination (Abdullah et al, EMBO J, 2017). The complex is attractive anticancer drug target. Moreover, mutations in components of the SLX4-complex are associated with (at least) three devastating monogenic inherited conditions: Fanconi anaemia, Xeroderma pigmentosum and Cockayne’s syndrome, associated with bone marrow failure, cancer predisposition, neurodegeneration and bone marrow failure. Our studies will also potentially illuminate the causes of these devastating conditions. We are combining structural studies with functional biochemistry and genetics and cellular phenotype analysis to provide an unparalleled insight into the structure and mechanism of one of the most important DNA repair complexes, which is critical to maintaining health, suppressing cancer and the hallmarks of ageing and which represents a highly attractive target in oncology.

Training will provided in cell biology, molecular biology techniques, bioinformatics and biochemistry. Depending upon the project pursued, advanced training will include cellular genetics/genome editing, advanced bioinformatics, advanced microscopy techniques, protein purification and biochemistry, structural biology (X-ray crystallography and cryo-electron microscopy), biophysical analysis, performing chemical and genetic screens and the characterisation of small molecule probes/inhibitors.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM.

Funding Notes

Funding for this project is available through the WIMM Prize Studentship, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

Applications must be received, including all relevant supporting materials, by Friday 11th January 2019 at 12 noon (midday).

Please visit our website for more information on how to apply.

References

Erdal E, Haider S, Rehwinkel J, Harris,AL and McHugh, PJ. A pro-survival DNA damage-induced cytoplasmic interferon response is mediated by end-resection factors, and is limited by Trex1. Genes Dev. 2017; 31(4):353-369

Abdullah UB, McGouran JF, Brolih S, Ptchelkine D, El-Sagheer AH, Brown T, and McHugh PJ*. RPA activates the XPF-ERCC1 endonuclease to initiate processing of DNA interstrand crosslinks. EMBO J, 2017, 14;36(14):2047-2060.

Lee SY, Brem J, Pettinati I, Claridge TDW, Gileadi O, Schofield CJ, and McHugh PJ* Cephalosporins Inhibit Human Metallo-ß-Lactamase Fold DNA Repair Nucleases SNM1A and SNM1B/Apollo. Chem Commun. 2016; 10;52(40):6727-30

Allerston CK, Lee SY, Newman JA, Schofield CJ, McHugh PJ, Gileadi O. The Structures of the SNM1A and SNM1B/Apollo nuclease domains revea a potential basis for their distinct DNA processing activities. Nucleic Acids Research, 2015, 15;43(22):11047-60

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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