Post-transcriptional regulation of gene expression in cancer.
We study post-transcriptional aspects of gene regulation, and specifically how these differ between cancer cells and their normal counterparts. One project in this area focuses on translation initiation factor eIF3e (also known as INT6), high levels of which in breast cancer are positively correlated with tumour grade. Our data indicate that eIF3e/INT6 selectively 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 in fission yeast. Our subsequent studies showed that Cid1 is a cytoplasmic protein with poly(A) polymerase activity in vitro, which may uridylate mRNAs in vivo. This modification forms the basis of a widespread but previously unappreciated pathway of mRNA degradation.
Human cells contain two Cid1 orthologues, one of which (ZCCHC11) we have found to be responsible for uridylation of replication-dependent histone mRNAs. The uridylation of histone mRNAs targets them for degradation after exposure of cells to hydroxyurea, an anti-cancer drug that inhibits DNA replication. ZCCHC11 is also 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 recent data suggest that 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.
Our recent collaborative study on the relationship between the structure of Cid1 and its function suggests ways in which RNA uridylyl transferases might be targeted therapeutically.
Nature Reviews Molecular Cell Biology 14: 643-653.
Nature Structural & Molecular Biology 19: 782-787.
RNA 17: 39-44.
Nature Structural & Molecular Biology 16: 616-623.