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The study shows that oncogene-induced replication stress is a major cause of genome instability in cancer cells. Overexpression of the cyclin E1 gene amplification causes replication stress in various cancers. PPM1D is a negative regulator of p53 and has been implicated in the termination of the cell cycle checkpoint. The study demonstrates that PPM1D activity further increases replication stress caused by overexpression of cyclin E1. The cells expressing a truncated mutant of PPM1D progress faster from G1 to the S phase and fail to complete licensing of replication origins. Additionally, transcription-replication collisions and replication fork slowing caused by CCNE1 overexpression are exaggerated in cells expressing the truncated PPM1D. Pharmacological inhibition of PPM1D rescues replication speed as well as accumulation of focal DNA copy number alterations caused by induction of CCNE1 expression. It is proposed that increased activity of PPM1D suppresses the checkpoint function of p53 and thus promotes genome instability in cells expressing the CCNE1 oncogene.
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