Chris has a long-standing interest in cell cycle regulation, particularly the roles played by cyclin-dependent protein kinases (CDKs) in cancer cells and their normal counterparts. More recent projects have identified additional proteins that regulate cell cycle checkpoints or drug resistance by influencing gene expression at post-transcriptional levels. Current work in collaboration with Shona Murphy brings these lines of investigation together and concerns the involvement of CDKs, particularly the archetypal cell cycle regulator CDK1, in the regulation of gene expression.
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Crystal structure of the Cid1 terminal uridylyl transferase (Yates et al., 2013) with bound UTP. Surface charge is colour-coded (red: acidic; blue: basic). RNA substrates are thought to bind via interaction with an extensive surface basic ‘stripe’.
Using genetic screens in the model organism Schizosaccharomyces pombe (fission yeast), novel determinants of cell cycle checkpoint control and drug resistance have been identified, and the roles of the human homologues of these genes have been followed up. One project in this area focused on translation initiation factor eIF3e (also known as INT6), which we found regulates the translation of mRNAs encoding a number of key regulators of tumour invasion and metastasis.
We identified Cid1, a nucleotidyl transferase which is required for cell cycle checkpoint activation when replicative DNA polymerases are inhibited. Our subsequent studies showed that Cid1 is a cytoplasmic protein that uridylates the 3’ ends of mRNAs in vivo. This modification forms the basis of a widespread but previously unappreciated pathway of mRNA degradation.
The human Cid1 orthologue ZCCHC11 (TUT4) is responsible for the modification of tumour suppressor micro-RNA precursors and mature micro-RNAs. Inhibition of ZCCHC11 expression in cancer cells blocks some of the aspects of the cancer phenotype in vivo, and ZCCHC11 over-expression predicts disease progression in breast cancer. Furthermore, lack of the DIS3L2 exonuclease, which preferentially destroys uridylylated cytoplasmic RNAs, predisposes to the development of Wilms’ tumour in early childhood. Targeting the ZCCHC11 uridylation pathway may therefore be of therapeutic value in a variety of cancers.
CDK1, the conserved, essential regulator of entry into mitosis, and its cyclin partners are frequently over-expressed in cancer cells. Recent studies suggest that CDK1 has additional, non-cell cycle functions and regulates transcription in embryonic stem cells. Our current work aims to test the hypothesis that CDK1 dysregulation also contributes to transcriptional re-programming during tumorigenesis. A close collaboration with Shona Murphy has led to the generation of cell lines expressing an ATP analogue-sensitive CDK1, which in living cells allows selective CDK1 inhibition and identification of its targets.
2023
Cyclin-dependent kinases: masters of the eukaryotic universe.
Pluta, A., Studniarek, C., Murphy, S. and Norbury, C.J.
WIREs RNA – (in press)
2023
Koller and the dawn of cancer cytogenetics.
Norbury, C.J.
British Journal of Cancer – 128: 402-403.
2013
Cytoplasmic RNA: a case of the tail wagging the dog.
Norbury, C.J.
Nature Reviews Molecular Cell Biology – 14: 643-653.
2012
Structural basis for the activity of a cytoplasmic RNA terminal uridylyl transferase.
Yates, L.A., Fleurdépine, S., Rissland, O.S., De Colibus, L., Harlos, K., Norbury, C.J. and Gilbert R.J.C.
Nature Structural & Molecular Biology – 19: 782-787.
2009
Decapping is preceded by 3′ uridylation in a novel pathway of bulk mRNA turnover.
Rissland, O.S. and Norbury, C.J.
Nature Structural & Molecular Biology – 16: 616-623.