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  Roles of negative transcriptional regulators in cancer cells


   Faculty of Biology, Medicine and Health

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  Dr Pawel Grzechnik, Dr Sankari Nagarajan  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Breast cancer is a widespread and life-threatening condition that affects millions of women globally. Understanding the complexity of gene expression associated with this disease is essential for developing targeted interventions that can revolutionize its diagnosis, treatment, and prevention. 

Deregulation of transcription factors is one the most common factors contributing to carcinogenesis as precise control of transcription and RNA processing is essential for the correct gene expression. While the activation of transcription is widely studied, knowledge about transcriptional repression is comparatively limited. The downregulation of transcription allows the reduction of gene expression by limiting RNA synthesis. This can be achieved by premature transcription termination, decreased transcription rates or increased promoter-proximal RNA Polymerase II (Pol II) pausing. The persistent presence of Pol II on the gene allows for a rapid shift from an “off” to “on” state when needed. Such transitions are essential for survival strategies including stress responses and cellular signalling. 

A successful candidate will study the functions of protein interacting with RPRD (Regulation of Nuclear mRNA Domain-Containing) proteins (RPRD1B, RPRD1A and RPRD2) which have been identified in our lab as negative transcription factors. RPRDs belong to the family of important transcriptional regulators interacting with RNA Polymerase II, are present on actively transcribed genes and their levels correlate with the cellular transcription rates. Most importantly these proteins are heavily overexpressed in breast cancer cells originating from primary and metastasis patients. 

Thus, the project will dissect the mechanistic details of how proteins interacting with RPRDs enforce transcription downregulation with a special focus on processes mediating the transition from transcription initiation to elongation in cancer cells.  

Training/techniques to be provided

Genome editing (CRISPR-cas9) 

- High-throughput RNA analyses (4sU-seq, chrRNA-seq, RNA-seq, NET-seq) 

- High-throughput Chromatin immunoprecipitation (ChIP-seq) 

- Bioinformatics 

- Protein purification

- Quantitative PCR 

- Western blotting 

- Standard molecular biology techniques (cloning, PCR, RT-PCR, etc.) 

Eligibility 

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject area. Applicants with Master's degree in Biological Sciences are encouraged to apply.

Before you Apply 

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.  

How to Apply 

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title - PhD Molecular Biology.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit https://www.bmh.manchester.ac.uk/study/research/international-phd/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]  

Equality, Diversity and Inclusion  

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/  

Biological Sciences (4)

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/