Investigating RNA cap regulation in colorectal cancer

Prof Vicky Cowling & Prof Owen Sansom

APPLY HERE

Labs: Gene Regulation and Colorectal Cancer and Wnt Signalling
Duration: 4 years, starting Oct 2023
Closing Date: 6th January 2023

Project Description

Colorectal cancer (CRC) is one of the most common cancers in the UK and a leading cause of cancer mortality. Recent advances have been made in the detection and treatment of early-stage disease, however, patients with advanced, recurrent or metastatic CRC have limited options for treatment. Like many cancers, colorectal cancer is a disease of molecular subgroups with different features and responses to therapy. By identifying key biochemical differences between the different types of CRC we hope to uncover and direct new therapeutic approaches.

Our analysis of CRC will focus on RNA cap formation, a critical stage in RNA maturation that directs which genes are expressed and as a result influences cell function, proliferation and fate decisions. We will use advanced mass spectrometry to analyse the RNA capping enzyme complexes in different tumour types. Biochemical analyses will be used to characterise RNA capping enzyme functions and advanced RNA/DNA sequencing methods will be used to analyse the role of these enzymes in gene regulation. We aim to understand how the RNA capping enzymes change in composition, activity and gene specificity as tumours initiate and progress from healthy tissue. This study will reveal the role of the RNA capping enzymes during tumour initiation and progression – and how best to target these enzymes in therapeutic approaches. We work closely with the Drug Discovery Unit and clinicians at the Beatson Institute to understand the clinical relevance of our findings.

This project will be carried out collaboratively in the labs of Vicky Cowling and Owen Sansom at the Beatson Institute, which have world-leading expertise in RNA capping enzymes and colorectal cancer research, respectively. The candidate should have an interest in gene regulation and its role in cancer. We are looking for a student with a very good degree in a Life Sciences subject and an aptitude for experimental work, who is committed to pursuing a PhD and a career in cancer research.

For informal enquiries or further details on the project, please contact Prof Vicky Cowling (victoria.cowling@glasgow.ac.uk)

APPLY HERE

References

Galloway A, Kaskar A, Ditsova D, Atrih A, Yoshikawa H, Moriera-Gomez C, Suska O, Warminski M, Grzela R, Lamond AI, Darzynkiewicz E, Jemeilty J and Cowling VH (2021) RNA cap methyltransferase RNMT promotes ribosome biogenesis via TOP-RNA in T cells Nucleic Acids Res. 2021 Jun 14:gkab465. 

Varshney D, Lombardi O, Schweikert G, Dunn S, Suska O and Cowling VH (2018) mRNA cap methyltransferase (RNMT-RAM) is required for RNA pol II-dependent transcription Cell Rep. 2018 May 1;23(5):1530-1542.

Knight JRP, Alexandrou C, Skalka GL, Vlahov N, Pennel K, Officer L, Teodosio A, Kanellos G, Gay DM, May-Wilson S, Smith EM, Najumudeen AK, Gilroy K, Ridgway RA, Flanagan DJ, Smith RCL, McDonald L, MacKay C, Cheasty A, McArthur K, Stanway E, Leach JD, Jackstadt R, Waldron JA, Campbell AD, Vlachogiannis G, Valeri N, Haigis KM, Sonenberg N, Proud CG, Jones NP, Swarbrick ME, McKinnon HJ, Faller WJ, Le Quesne J, Edwards J, Willis AE, Bushell M, Sansom OJ. MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression. Cancer Discov. 2021;11(5):1228-1247

Knight JR, Vlahov N, Gay DM, Ridgway RA, Faller WJ, Proud C, Mallucci GR, von der Haar T, Smales CM, Willis AE, Sansom OJ. Rpl24(Bst) mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K. Elife. 2021;10.

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