Dr Cyril Sanders
Dr Sander’s studies viral and cellular eukaryotic replication proteins to understand mechanisms of DNA replication. His research currently focuses on two areas:
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 subset of these are associated with cancer (e.g. HPV16 and 18 are known for their involvement in cervical cancer). The viral E1 protein is a replication initiator protein and hexameric replicative helicases. The role of the helicase in replication is to unwind double stranded DNA to provide a template for DNA polymerase. The focus of Dr Sander’s current research is to combine biochemical and biophysical techniques (EM, X-ray crystallography, SAXS) to understand how E1 replication machines assemble, translocate on DNA and separate DNA base pairs.
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. 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, the hPIF1 helicase has been identified as a potential target for cancer therapy. The lab’s in vitro studies indicate that hPif has a role in the maintenance of replication fork integrity. Dr Sanders group have initiated a drug discovery campaign and are screening small molecule libraries for inhibitors of PIF1 function.
- Chaban Y, Stead JA, Ryzhenkova K, Whelan F, Lamber EP, Antson A, Sanders CM, Orlova EV. (2015)
Structural basis for DNA strand separation by a hexameric replicative helicase.
Nucleic Acids Res. 2015 Sep 30;43(17):8551-63. doi: 10.1093/nar/gkv778.
- Wong IN, Sayers JR, Sanders CM. (2013)
Characterization of an unusual bipolar helicase encoded by bacteriophage T5.
Nucleic Acids Res. 41: 4587-600. doi: 10.1093/nar/gkt105.
- Whelan F, Stead JA, Shkumatov AV, Svergun DI, Sanders CM, Antson AA. (2012)
A flexible brace maintains the assembly of a hexameric replicative helicase during DNA unwinding.
Nucleic Acids Res. 40: 2271-83. doi: 10.1093/nar/gkr906.
- Gagou ME, Ganesh A, Thompson R, Phear G, Sanders C, Meuth M. (2011)
Suppression of apoptosis by PIF1 helicase in human tumor cells.
Cancer Res. 71: 4998-5008. doi: 10.1158/0008-5472.CAN-10-4404.
- Sanders CM. (2010)
Human Pif1 helicase is a G-quadruplex DNA-binding protein with G-quadruplex DNA-unwinding activity.
Biochem J. 430: 119-28. doi: 10.1042/BJ20100612.
- George T, Wen Q, Griffiths R, Ganesh A, Meuth M, Sanders CM. (2009)
Human Pif1 helicase unwinds synthetic DNA structures resembling stalled DNA replication forks.
Nucleic Acids Res. 37: 6491-502. doi: 10.1093/nar/gkp671.
- Sanders CM. (2008)
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: 1891-9. doi: 10.1093/nar/gkn041.
- Sanders CM, Kovalevskiy OV, Sizov D, Lebedev AA, Isupov MN, Antson AA. (2007)
Papillomavirus E1 helicase assembly maintains an asymmetric state in the absence of DNA and nucleotide cofactors.
Nucleic Acids Res. 35: 6451-7.
- Sanders CM, Sizov D, Seavers PR, Ortiz-Lombard M, Antson AA. (2007)
Transcription activator structure reveals redox control of a replication initiation reaction. Nucleic Acids Res. 35: 3504-15.