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What determines tumour susceptibility to replication-inhibiting chemotherapy?

Project Description

Chromosome replication and maintenance are central for cell division, and derailment of these processes is a major cause of cancer. The protein RIF1 has emerged as a conserved regulator of chromosome maintenance, acting to control DNA replication and repair. We have discovered that RIF1 is needed for cellular survival after treatment with chemotherapeutic drugs that induce replication stress, acting in a pathway separate from the well-established RIF1 functions in replication and repair. However how RIF1 ensures cellular recovery from replication stress remains mysterious. We have however found that of the two known splice variant isoforms of human RIF1, only one can mediate recovery from replication stress. This PhD project will investigate the mechanism through which RIF1 mediates recovery from replication stress, identifying the mechanism through which only one of the two RIF1 isoforms promotes cell survival.

Interestingly, it has been suggested that the RIF1 isoform expression profile changes during carcinogenesis. Many of the most commonly used cancer chemotherapeutics act by blocking replication forks to induce replication stress, raising the possibility that examining RIF1 isoform expression in tumours may allow prediction of their response to this class of chemotherapeutics. Alongside testing the mechanism by which RIF1 protects cells from replication stress, the student will test RIF1 isoform expression in patient-derived tumour samples. Our long-term aim is to develop a new assay for the usefulness to replication-inhibiting chemotherapy, allowing optimisation of the therapy regime for specific patients according to the molecular characteristics of their specific cancer.

Benefiting from an advisory team comprising a basic scientist and a clinical pathologist, this project exploits the location of the Institute of Medical Sciences at Aberdeen Royal Infirmary, and the resulting opportunities for productive collaboration and exploitation of fundamental understanding.

This project is advertised in relation to the research areas of MEDICAL SCIENCES. Formal applications can be completed online: You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM. Applicants are limited to applying for a maximum of 3 applications for funded projects. Any further applications received will be automatically withdrawn.

Funding Notes

This project is funded by a University of Aberdeen Elphinstone Scholarship. An Elphinstone Scholarship covers the cost of tuition fees only, whether home, EU or overseas.

For details of fees: View Website

Candidates should have (or expect to achieve) a minimum of a First Class Honours degree in a relevant subject. Applicants with a minimum of a 2:1 Honours degree may be considered provided they have a Distinction at Masters level.


S. Hiraga, G.M. Alvino, F. Chang, H. Lian, A. Sridhar, T. Kubota, B.J. Brewer, M. Weinreich, M.K. Raghuraman & A.D. Donaldson (2014). Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex. Genes & Development 28: 372

S.Hiraga, T. Ly, J. Garzon, Z. Hořejší, M. Okubo, A. Endo, C. Obuse, S.J. Boulton, A.I. Lamond and A.D. Donaldson (2017). Human RIF1 and Protein Phosphatase 1 stimulate DNA replication origin licensing but suppress origin activation. EMBO Reports 18: 403

J. Garzón, C. Monerawela, S. Ursich, M. Lopes, S. Hiraga and A.D. Donaldson (2019). RIF1-Protein Phosphatase 1 prevents degradation and breakage of nascent DNA on replication stalling. Cell Reports, 27: 2558-2566.e4

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