Speaker
Dr
Dianov Grigory
(University of Oxford)
Description
The deubiquitylation enzyme USP7 (also known as HAUSP) plays a major role in regulating genome stability and cancer prevention by controlling the key proteins involved in the cellular DNA damage response, including Mdm2, p53, FOXO4 and PTEN. Deletion of USP7 leads to early embryonic lethality mainly due to increased p53 levels and cell proliferation arrest. Despite such an important role in controlling other DNA damage response proteins, USP7 itself has not been recognised as a target for regulation by DNA damage signalling pathways. We have recently found that USP7 regulation plays a central role in DNA damage signal transmission. We discovered that stabilisation of Mdm2, and correspondingly p53 down-regulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine eighteen by the protein kinase CK2. Phosphorylation at serine eighteen stabilises USP7S and thus contributes to Mdm2 stabilisation and down-regulation of p53. Furthermore, following treatment of cells with ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S down-regulation, followed by Mdm2 down-regulation and accumulation of p53. Interruption of this DNA damage signalling by PPM1G knockdown leads to improper coordination between DNA repair and replication, thus resulting in cell cycle arrest. Our findings uncover a novel DNA damage signal transduction pathway linking ATM, PPM1G and USP7S, and provide the mechanism as to how the DNA damage signal is quantitatively transmitted to coordinate a p53-dependent DNA damage response.
Primary author
Dr
Dianov Grigory
(University of Oxford)
