PPM1D activity promotes the replication stress caused by cyclin E1 overexpression

Oncogene-induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. The PPM1D phosphatase is a negative regulator of p53 and its increased expression or gain-of-function mutations can promote tumorigenesis. Here, we show that PPM1D activity further increases the replication stress caused by overexpression of cyclin E1. In particular, we demonstrate that cells expressing the truncated mutant of PPM1D progress faster from G1 to S phase and fail to complete licensing of the replication origins. As a consequence, replication fork slowing caused by cyclin E1 overexpression is further pronaunced in cells expressing truncated PPM1D. Importantly, replication speed as well as accumulation of the focal DNA copy number alterations caused by induction of cyclin E1 expression was rescued by pharmacological inhibition of PPM1D. We propose that increased activity of PPM1D suppresses the checkpoint function of p53 and thus promotes genome instability in cells expressing the CCNE1 oncogene.