Dr Cyril Sanders

BSc, PhD

Department of Oncology and Metabolism

Reader in Molecular Genetics of Cancer

c.m.sanders@sheffield.ac.uk
+44 114 215 9060

Full contact details

Dr Cyril Sanders
Department of Oncology and Metabolism
GU17, G Floor
The Medical School
Beech Hill Road
Sheffield
S10 2RX
Profile

For enquiries, please contact - om-operationalteam@sheffield.ac.uk

BSc. University of Bristol, UK

PhD. University of York, UK

Postdoctoral Research Fellow, Cold Spring Harbor Laboratory, NY, USA
- Wellcome International Prize Travelling Fellowship, 1996-1997, Cold Spring Harbor Laboratory, USA
- Joseph G. Goldring Foundation Fellowship, 1999, Cold Spring Harbor laboratory USA

Lecturer in Cancer Studies, Institute for Cancer Studies, University of Sheffield, UK

Senior Lecturer in Cancer Studies, Institute for Cancer Studies, University of Sheffield, UK

Senior Lecturer in Cancer Studies, Department of Oncology, University of Sheffield, UK

Reader in Molecular Genetics of Cancer, Department of Oncology & Metabolism, University of Sheffield, UK

Research interests
  • Replication and gene regulation in papillomavirus
  • Structure and function of helicases and replication/transcription control proteins
  • DNA helicases involved in the DNA damage response and their potential as therapeutic targets in cancer

Current projects

STRUCTURE AND FUNCTION OF THE PAPILLOMAVIRUS E1 HELICASE

The papillomaviruses are a large group of small DNA viruses that infect many species. There are over 100 types identified in man and a small subset of these are associated with cancer. HPV16 and 18 in particular are known for their involvement in cervical cancer, but it has been estimated that up to 5% of all cancer in humans may be the result of HPV infection. Other viral types are the causative agents of warts. Overall, the HPV disease burden has a considerable impact on wellbeing and is costly to healthcare agencies. Classically, bovine papillomavirus (BPV-1) has been the model for the papillomavirus family. It forms large fibroepithelial tumours containing large quantities of infectious particles. BPV-1 DNA was the first to be molecularly cloned and manipulated and transformation assays were established in the early 1960s. The BPV proteins involved in gene control and replication have proven to be highly tractable to molecular analysis compared to the counterparts in HPV. This is particularly true of the viral E1 protein, which is a replication initiator protein and hexameric replicative helicases. The role of the helicase in replication is to separate the strands of double stranded DNA to provide a template for DNA polymerase. The focus of our current research is to combine biochemical and biophysical techniques (EM, X-ray crystallography, SAXS, NMR etc.) to understand how E1 replication machines assemble, translocate on DNA and separate DNA base pairs.

Funding

BBSRC
“Structure of origin DNA melting and unwinding complexes of a viral replication protein”
in collaboration with E. Orlova, Birkbeck College London.

BBSRC
“Opening of a double stranded DNA replication fork by a hexameric helicase”
in collaboration with A. Antson, University of York, York Structural Biology Laboratory.

ROLE OF THE HUMAN HELICASE PIF1 IN GENOME STABILITY

Helicases, particularly those belonging to superfamily 1 and 2 have roles in the DNA damage and DNA repair responses. This is underpinned by observations that RecQ helicases are required for genetic stability and that some helicases are sharply up-regulated in human tumours. The essential function provided by these helicases is likely to be the recognition and unwinding of replication intermediates (e.g. recombination substrates and stalled replication forks) and non-canonical DNA structures such as quadruplex (G4) and triplex DNA. Recently, research in our unit (Prof. M. Meuth and co-workers) has shown that siRNA-mediated hPIF1 depletion reduced the survival of several tumour cell lines by triggering apoptosis while non-tumour lines were unaffected. Tumour cell death was augmented by treatment with replication inhibitors, including the anti-cancer drug gemcitabine. Our in vitro studies with purified recombinant hPIF1 show unwind of a variety of DNA structural forms including synthetic stalled DNA replication fork-like structures and G4 DNA that can potentially stall DNA replication forks. Taken together, our results suggest roles for hPIF1 in S-phase entry and progression, possibly mediated through the maintenance of replication fork integrity, that protect some human tumour cells from apoptosis. The focus of our current research is to understand the precise role of PIF1 in genome stability by characterizing substrate interactions. We have initiated a drug discovery campaign and are screening small molecule libraries for inhibitors of PIF1 function.

Funding

Yorkshire Cancer Research
“Genetic instability and death in cancer cells”
Programme grant, Cox A., Catto, J., Bryant, H., Sanders, C., Meuth, M.

MRCT
“A small molecule screen for inhibitors of human PIF1 action”

Publications

Show: Featured publications All publications

Journal articles

All publications

Journal articles

Research group

S.Dehghani-Tafti - Post Graduate Student