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Genetic Instability

Genetic Instability is an enabling cancer phenotype associated with nearly all tumours. Sheffield has a strong tradition in basic research that aims to uncover the fundamental mechanisms through which DNA integrity is maintained, and to subsequently discover how their dysregulation contributes to cancer.

The work of several PIs is integrated in the YCR Institute for Cancer Studies in the Department of Oncology, where the groups of Dr Helen Bryant, Dr Spencer Collis, Professor Mark Meuth and Dr Cyril Sanders investigate the molecular mechanisms of DNA replication and remodelling, DNA damage detection and repair, while cancer-associated protein kinases that control cell cycle checkpoints are the subject of pre-clinical work in Dr Patrick Eyers’ lab. Elsewhere in the University this work is complemented by the research groups of Dr Alastair Goldman, Professor Stuart Wilson, Dr Karen Sisley and Professor Carl Smythe, who each investigate how distinct normal and cancer cell types maintain genomic integrity and mRNA stability.

High-resolution genomic analysis of inherited and tumour-specific DNA variations associated with cancer is led by Professor Angie Cox, and Professor Jim Catto’s laboratory investigates global cancer epigenetics and the function of micro RNAs in model and clinical cancer settings.
An increasingly important aspect of all our work involves the translation of basic biological findings into the pre-clinical and clinical arenas. Indeed, it has become apparent in the past decade that drug-like molecules that interfere with abnormal signalling pathways regulating DNA integrity have the potential to be important in the clinic, where DNA damaging agents still represent the major class of cytotoxic agent administered to patients. For example, small molecule inhibitors of the repair enzyme PARP have shown significant potential for killing tumour cells that rely on specific DNA repair pathways, whilst leaving normal cells largely untouched. Such targeted strategies, originally pioneered in Sheffield and currently the subject of national and international clinical trials, are driven by research findings from our laboratories and represent major future goals.