North West Cancer Research PhD Studentship: Analysis of the role of unbiquitylation of Ciz1 in regulation of DNA replication and cell division
We are offering a fully funded studentship by NorthWest Cancer Research under the supervision of Dr Nikki Copeland, including a stipend of £19,000 p.a. for three years. Please contact Dr Copeland including a CV and covering letter in the first instance. The studentship is open to all UK and EU candidates who meet residency requirements. Applications from ineligible candidates will not be considered.
Deadline for applications: 28th August 2015
Interviews will take place on 10th September 2015
Precise regulation of DNA replication is essential for maintenance of a healthy genome. The periodic activation of cyclin dependent protein kinases and their destruction by ubiquitylation and proteasomal degradation ensures strict control of the cell cycle. Cyclin A-CDK2 cooperates with Ciz1 to promote initiation of DNA replication 1, 2 and has been implicated in promoting tumour growth. Overexpression of Ciz1 supports tumour growth in breast cancer, colorectal cancer and lung cancer 3-6. Importantly, siRNA mediated depletion of Ciz1 reduced tumour growth in breast, lung and colorectal cancer3, 4, 6, suggesting that strategies that reduce Ciz1 protein levels may also reduce tumour growth. The ubiquitin proteasome system (UPS) plays a key role in regulation of cell cycle proteins, which ensures that their activity is restricted to defined points in the cell cycle. Cancer associated overexpression of E3 ligases and F-box proteins have been associated with increased proliferation due to alterations in expression of cell cycle regulators7. This work aims to determine how CDK mediated phosphorylation and ubiquitylation regulates Ciz1 protein levels and identify the regulatory ubiquitin E3 ligase that mediates this process. The aims of this project are to:
(i) Analyse the interplay between CDK mediated phosphorylation and ubiquitylation in regulation of Ciz1 and cell division
(ii) Identify the ubiquitin E3 ligase(s) that regulate Ciz1 protein levels
(iii) Investigate how misregulated Ciz1 levels promotes tumour growth
 Copeland, N. A., Sercombe, H. E., Wilson, R. H., and Coverley, D. (2015) Cyclin-A-CDK2-mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication, J Cell Sci 128, 1518-1527.
 Copeland, N. A., Sercombe, H. E., Ainscough, J. F., and Coverley, D. (2010) Ciz1 cooperates with cyclin-A-CDK2 to activate mammalian DNA replication in vitro, J Cell Sci 123, 1108-1115.
 den Hollander, P., Rayala, S. K., Coverley, D., and Kumar, R. (2006) Ciz1, a Novel DNA-binding coactivator of the estrogen receptor alpha, confers hypersensitivity to estrogen action, Cancer Res 66, 11021-11029.
 Higgins, G., Roper, K. M., Watson, I. J., Blackhall, F. H., Rom, W. N., Pass, H. I., Ainscough, J. F., and Coverley, D. (2012) Variant Ciz1 is a circulating biomarker for early-stage lung cancer, Proc Natl Acad Sci U S A 109, E3128-3135.
 Wang, D. Q., Wang, K., Yan, D. W., Liu, J., Wang, B., Li, M. X., Wang, X. W., Liu, J., Peng, Z. H., Li, G. X., and Yu, Z. H. (2014) Ciz1 is a novel predictor of survival in human colon cancer, Exp Biol Med (Maywood) 239, 862-870.
 Yin, J., Wang, C., Tang, X., Sun, H., Shao, Q., Yang, X., and Qu, X. (2013) CIZ1 regulates the proliferation, cycle distribution and colony formation of RKO human colorectal cancer cells, Molecular medicine reports 8, 1630-1634.
 Wang, Z., Liu, P., Inuzuka, H., and Wei, W. (2014) Roles of F-box proteins in cancer, Nature reviews. Cancer 14, 233-247.
ESRC-Funded Research Studentships
Lancaster University forms part of the Economic and Social Research Council (ESRC)'s North West Doctoral Training Centre (NWDTC). A large number of studentships, covering tuition and maintenance, are available for those wishing to study in areas covered by the ESRC at Lancaster, Liverpool or Manchester. Some studentships are reserved for students seeking joint supervision across two or more partner institutions.
Details of the provision and funding offered by the NWDTC are available here.
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