Dr Cyril Sanders
BSc, PhD
Clinical Medicine, School of Medicine and Population Health
Reader in Molecular Genetics of Cancer
+44 114 215 9060
Full contact details
Clinical Medicine, School of Medicine and Population Health
GU17, G Floor
The Medical School
Beech Hill Road
Sheffield
S10 2RX
- Profile
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For enquiries please contact - ClinMed-Operational@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 USALecturer 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, School of Medicine & Population Health, University of Sheffield, UK
- Research interests
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- 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
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Show: Featured publications All publications
Featured publications
Journal articles
- DNA substrate recognition and processing by the full-length human UPF1 helicase. Nucleic Acids Research, 45(12), 7354-7366. View this article in WRRO
- Bacteriophage T5 gene D10 encodes a branch-migration protein. Scientific Reports, 6. View this article in WRRO
- Structural basis for DNA strand separation by a hexameric replicative helicase. Nucleic Acids Research, 43(17), 8551-8563. View this article in WRRO
- Characterization of an unusual bipolar helicase encoded by bacteriophage T5.. Nucleic Acids Res, 41(8), 4587-4600. View this article in WRRO
- A flexible brace maintains the assembly of a hexameric replicative helicase during DNA unwinding.. Nucleic Acids Res. View this article in WRRO
- Human Pif1 helicase is a G-quadruplex DNA-binding protein with G-quadruplex DNA-unwinding activity.. Biochem J, 430(1), 119-128.
- Human Pif1 helicase unwinds synthetic DNA structures resembling stalled DNA replication forks.. Nucleic Acids Res, 37(19), 6491-6502. View this article in WRRO
- A DNA-binding activity in BPV initiator protein E1 required for melting duplex ori DNA but not processive helicase activity initiated on partially single-stranded DNA.. Nucleic Acids Res, 36(6), 1891-1899. View this article in WRRO
- Papillomavirus E1 helicase assembly maintains an asymmetric state in the absence of DNA and nucleotide cofactors.. Nucleic Acids Res, 35(19), 6451-6457. View this article in WRRO
- Transcription activator structure reveals redox control of a replication initiation reaction.. Nucleic Acids Res, 35(10), 3504-3515. View this article in WRRO
- Role of ATP hydrolysis in the DNA translocase activity of the bovine papillomavirus (BPV-1) E1 helicase.. Nucleic Acids Res, 34(13), 3731-3741. View this article in WRRO
- Common determinants in DNA melting and helicase-catalysed DNA unwinding by papillomavirus replication protein E1.. Nucleic Acids Res, 34(10), 3008-3019. View this article in WRRO
- Structure of the intact transactivation domain of the human papillomavirus E2 protein.. Nature, 403, 805-809.
- Suppression of apoptosis by PIF1 helicase in human tumour cells, 71, 4998-5008.
All publications
Journal articles
- Structure-based discovery of first inhibitors targeting the helicase activity of human PIF1. Nucleic Acids Research, gkae897.
- Unwinding of a DNA replication fork by a hexameric viral helicase. Nature Communications, 12(1).
- Unwinding of a DNA replication fork by a hexameric viral helicase. Nature Communications.
- Structural and functional analysis of the nucleotide and DNA binding activities of the human PIF1 helicase. Nucleic Acids Research, 47(6), 3208-3222. View this article in WRRO
- DNA substrate recognition and processing by the full-length human UPF1 helicase. Nucleic Acids Research, 45(12), 7354-7366. View this article in WRRO
- Bacteriophage T5 gene D10 encodes a branch-migration protein. Scientific Reports, 6. View this article in WRRO
- Structural basis for DNA strand separation by a hexameric replicative helicase. Nucleic Acids Research, 43(17), 8551-8563. View this article in WRRO
- Characterization of an unusual bipolar helicase encoded by bacteriophage T5.. Nucleic Acids Res, 41(8), 4587-4600. View this article in WRRO
- A flexible brace maintains the assembly of a hexameric replicative helicase during DNA unwinding.. Nucleic Acids Res. View this article in WRRO
- Human Pif1 helicase is a G-quadruplex DNA-binding protein with G-quadruplex DNA-unwinding activity.. Biochem J, 430(1), 119-128.
- Human Pif1 helicase unwinds synthetic DNA structures resembling stalled DNA replication forks.. Nucleic Acids Res, 37(19), 6491-6502. View this article in WRRO
- A DNA-binding activity in BPV initiator protein E1 required for melting duplex ori DNA but not processive helicase activity initiated on partially single-stranded DNA.. Nucleic Acids Res, 36(6), 1891-1899. View this article in WRRO
- Papillomavirus E1 helicase assembly maintains an asymmetric state in the absence of DNA and nucleotide cofactors.. Nucleic Acids Res, 35(19), 6451-6457. View this article in WRRO
- Transcription activator structure reveals redox control of a replication initiation reaction.. Nucleic Acids Res, 35(10), 3504-3515. View this article in WRRO
- High-specific-activity probes and a high-resolution in-gel photo cross-linking assay for protein-DNA complexes.. Anal Biochem, 359(2), 203-209.
- Role of ATP hydrolysis in the DNA translocase activity of the bovine papillomavirus (BPV-1) E1 helicase.. Nucleic Acids Res, 34(13), 3731-3741. View this article in WRRO
- Common determinants in DNA melting and helicase-catalysed DNA unwinding by papillomavirus replication protein E1.. Nucleic Acids Res, 34(10), 3008-3019. View this article in WRRO
- Mechanism and requirements for Bovine papillomavirus Type I E1 initiator complex assembly promoted by the E2 transcription factor bound to distal sites.. J. Biol. Chem, 276, 23689-23699.
- Transcription factor dependent-loading of the E1 initiator reveals modular assembly of the papillomavirus origin melting complex. J. Biol. Chem, 275, 3522-3534.
- Structure of the intact transactivation domain of the human papillomavirus E2 protein.. Nature, 403, 805-809.
- Expression patterns of the human papillomavirus type 16 transcription factor E2 in low- and high-grade cervical intraepithelial neoplasia. J PATHOL, 186(3), 275-280.
- Characterisation of the interactions of human papillomavirus type 16 E6 with p53 and E6-associated protein in insect and human cells.. Journal of General Virology, 79, 489-499.
- Expression, crystallisation and preliminary X-ray analysis of the E2 transactivation domain from papillomavirus type 16.. Acta. Crystallog. D. Biol. Crystallogr., 54, 1471-1474.
- Recruitment and loading of the E1 initiator protein: an ATP-dependent process catalysed by a transcription factor.. EMBO J., 17, 7044-7055.
- Differences in serological IgA responses to recombinant baculovirus-derived human papillomavirus E2 protein in the natural history of cervical neoplasia.. British Journal of Cancer, 75, 1144-1150.
- Molecular analysis of the interaction between HPV type 16 E6 and human E6-associated protein.. FEBS Letters, 416, 6-10.
- Human papillomavirus DNA and TP53 mutations in lung cancer from butchers. British Journal of Cancer, 72, 293-324.
- Characterisation of human papillomavirus type 16 E2 protein and sub-domains expressed in insect cells. virology, 211, 418-433.
- A polymerase chain reaction (PCR) investigation of cutaneous HPV types in oral verrucae. Journal of Oral Pathology, 24, 329-324.
- Butchers' warts: no evidence for person to person transmission of HPV 7. British Journal of Dermatology, 130, 15-17.
- Cutaneous warts in butchers. British Journal of Dermatology, 130, 9-14.
- Kinetic and equilibrium binding studies of the human papillomavirus type 16 transcription regulatory protein E2 interacting with core enhancer elements.. Nucleic Acids Research, 22, 4890-4897.
- Detection of human papilloma virus type 16 DNA in oral squames from normal young adults. Journal of Oral Pathology and Medicine, 21(10), 465-470.
- Suppression of apoptosis by PIF1 helicase in human tumour cells, 71, 4998-5008.
- DNA substrate recognition and processing by the full-length human UPF1 helicase. Nucleic Acids Research, 45(12), 7354-7366. View this article in WRRO
- Research group
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S.Dehghani-Tafti - Post Graduate Student