RNA terminal U-transferases in cancer development
The cytoplasmic RNA terminal uridylyl transferase (TUT) ZCCHC11 promotes tumour growth, at least in part by 3' uridylylation of let-7 tumour suppressor microRNA precursors, blocking their maturation and hence driving stem cell-like self-renewal. Furthermore, lack of the DIS3L2 exonuclease, which preferentially destroys uridylylated cytoplasmic RNAs, predisposes to the development of Wilms' tumour in early childhood. Despite these clear links to tumorigenesis, RNA uridylylation and its biological consequences are only partially understood.
This project will address aspects of the following key questions, according to the interests of the student, as part of a larger programme of ongoing research:
(i) What are the uridylylated RNA substrates that accumulate in such a way as to promote tumorigenesis in the absence of DIS3L2, and are these RNAs uridylylated by ZCCHC11 and/or its orthologue ZCCHC6?
(ii) How do ZCCHC11 and ZCCHC6 bind their RNA and UTP substrates?
(iii) To what extent do other proteins with which these TUTs interact determine their substrate specificities?
Site-directed mutagenesis will be used to explore the mechanisms by which ZCCHC11 and ZCCHC6 bind their RNA and UTP substrates. HITS-CLIP and sequencing (RIP-seq) along with allied techniques will be used to characterise targets of DIS3L2, ZCCHC6 and ZCCHC11 in mouse fibroblasts and human breast cancer cells. Proteins interacting with the uridylyl transferases will be identified by mass spectrometry, and the ways in which these proteins influence the activity, substrate recruitment and subcellular localisation of ZCCHC6 and ZCCHC11 will be determined.
This project is expected to provide important new insights into the ways in which both aberrant RNA uridylylation and the failure to degrade uridylylated RNAs contribute to cancer development, and to test the hypothesis that small molecule inhibitors of ZCCHC11 would be of therapeutic benefit.
If you have any queries about this position, or would like to apply for your own postdoctoral fellowship to work in the laboratory, please contact Chris Norbury.
Last updated October 2014