My laboratory has a long interest in how translation regulation controls gene expression and how this is perturbed in human diseases. In particular, how microRNAs regulate gene expression and we have specifically focused on their role following DNA damage. The DNA damage response activates several pathways that stall the cell cycle and allow DNA repair. These consist of the well characterised ATR/CHK1 and ATM/CHK2 pathways in addition to a newly identified ATM/ATR/p38MAPK/MK2 checkpoint. The p38MAPK/MK2 checkpoint has been found to be particularly important for DNA repair in cells lacking functional p53 and inhibition of the MK2 checkpoint leads to mitotic catastrophe, however the downstream targets of this pathway have not been fully identified.
Recently, we have shown that following etoposide-induced DNA damage translation of c-Myc is repressed by miR-34c via a highly conserved target-site within the 3'UTR. While miR-34c is induced by p53 following DNA damage, we have shown that in cells lacking p53 this is achieved by an alternative pathway which involes p38 MAPK signalling to MK2. Our data suggests that a major physiological target of miR-34c is c-Myc, demonstrating that miR-34c is a critical regulator of c-Myc expression following DNA damage acting downstream of p38 MAPK/MK2 and suggests that miR-34c serves to remove c-Myc to prevent inappropriate replication which may otherwise lead to genomic instability.
We are now concentrating on determining the mechanisms by which c-Myc drives DNA damage, addressing whether the MK2 checkpoint requires the induction of miR-34c and investigating whether microRNA-based therapeutics to miR-34c could be an effective treatment for certain types of cancer.