Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates cell response to genotoxic stress by negatively regulating the tumor suppressor p53 and other targets at chromatin. Mutations in the exon 6 of the PPM1D result in production of a highly stable, C-terminally truncated PPM1D. These gain-of-function PPM1D mutations are present in various human cancers but their role in tumorigenesis remains unresolved. Here we show that truncated PPM1D impairs activation of the cell cycle checkpoints in human non-transformed RPE cells and allows proliferation in the presence of DNA damage. Next, we developed a mouse model by introducing a truncating mutation in the PPM1D locus and tested contribution of the oncogenic PPM1DT allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1DT resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in Apcmin mice and diminished survival. Moreover, tumor organoids derived from colon of the ApcminPpm1dT/+ mice were less sensitive to 5-fluorouracil when compared to ApcminPpm1d+/+and the sensitivity to 5-fluorouracil was restored by inhibition of PPM1D. Finally, we screened colorectal cancer patients and identified recurrent somatic PPM1D mutations in a fraction of colon adenocarcinomas that are p53 proficient and show defects in mismatch DNA repair. In summary, we provide the first in vivo evidence that truncated PPM1D can promote tumor growth and modulate sensitivity to chemotherapy.

Biomedical Centre Faculty of Medicine in Pilsen Charles University Prague Czech Republic

Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Cell and Developmental Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department Molecular Oncology Institute for Cancer Research and K G Jebsen Colorectal Cancer Research Centre Oslo University Hospital Oslo Norway

Department of Abdominal Thoracic Surgery and Traumatology 1st Faculty of Medicine Charles University and General Faculty Hospital Prague Prague Czech Republic

Department of Endocrinology and Metabolism 1st Faculty of Medicine Charles University and General Faculty Hospital Prague Prague Czech Republic

Department of Oncology and Department of Clinical and Experimental Medicine Linköping University Linköping Sweden

Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Biology and Medical Genetics 1st Medical Faculty Charles University Prague Czech Republic

Institute of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Molecular Biology of Cancer Institute of Experimental Medicine ASCR Prague Czech Republic

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