The Fanconi anaemia pathway and cancer: a molecular dissection

Primary Supervisor: Prof Peter McHugh

Second Supervisor: Joseph Newman, CMD

Project Overview

The inherited syndrome Fanconi anaemia (FA) produces devastating and often lethal clinical features including bone marrow failure, developmental defects and solid and haematological malignancies. The cellular defect in FA is an inability to purge the genome of DNA interstrand crosslinks (ICLs), using the ‘FA’ DNA repair pathway. ICLs are amongst the most toxic forms of DNA damage known and arise when duplex DNA strands become covalently linked, blocking fundamental cellular processes including transcription and DNA replication.

Despite advances in identifying key components and some landmark steps, the molecular details of how the FA pathway co-ordinate to ICL processing removal are obscure. Here, we will bring together a powerful combination of nucleic acid and protein biochemistry with structural and molecular biology to reveal the mechanistic details of FA pathway operation. By studying this repair pathway in unprecedented detail and depth, we will transform our understanding of the FA and open up new avenues to treat patients. The genes defective in FA are also closely linked with predisposition to disease in the population more generally and are potential therapeutic targets, including against cancer, and our work will be vital to realising the potential of targeting the FA pathway.

Training Opportunities

The student will be trained in cell biology, genetics, protein purification and analysis, reconstitution biochemistry, single molecule studies, cryogenic electron-microscopy.

References:

1. Nalepa, G. and Clapp, D.W., 2018. Fanconi anaemia and cancer: an intricate relationship. Nature Reviews Cancer, 18(3), pp.168-185.Moon, E.J. and Giaccia, A., 2015. Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. Free Radical Biology and Medicine, 79, pp.292-299.
2. Abdullah, U.B., McGouran, J.F., Brolih, S., Ptchelkine, D., El‐Sagheer, A.H., Brown, T. and McHugh, P.J., 2017. RPA activates the XPF‐ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks. The EMBO journal, 36(14), pp.2047-2060.