The DNA damage response (DDR) pathway and its core component tumor suppressor p53 block cell cycle progression after genotoxic stress and represent an intrinsic barrier preventing cancer development. The serine/threonine phosphatase PPM1D/Wip1 inactivates p53 and promotes termination of the DDR pathway. Wip1 has been suggested to act as an oncogene in a subset of tumors that retain wild-type p53. In this paper, we have identified novel gain-of-function mutations in exon 6 of PPM1D that result in expression of C-terminally truncated Wip1. Remarkably, mutations in PPM1D are present not only in the tumors but also in other tissues of breast and colorectal cancer patients, indicating that they arise early in development or affect the germline. We show that mutations in PPM1D affect the DDR pathway and propose that they could predispose to cancer.

Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University Prague CZ 12853 Prague Czech Republic

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Agami R., Bernards R. 2000. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell. 102:55–66 10.1016/S0092-8674(00)00010-6 PubMed DOI

Bartkova J., Horejsí Z., Koed K., Krämer A., Tort F., Zieger K., Guldberg P., Sehested M., Nesland J.M., Lukas C., et al. 2005. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 434:864–870 10.1038/nature03482 PubMed DOI

Bartkova J., Rezaei N., Liontos M., Karakaidos P., Kletsas D., Issaeva N., Vassiliou L.-V.F., Kolettas E., Niforou K., Zoumpourlis V.C., et al. 2006. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 444:633–637 10.1038/nature05268 PubMed DOI

Bulavin D.V., Demidov O.N., Saito S.i., Kauraniemi P., Phillips C., Amundson S.A., Ambrosino C., Sauter G., Nebreda A.R., Anderson C.W., et al. 2002. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat. Genet. 31:210–215 10.1038/ng894 PubMed DOI

Bulavin D.V., Phillips C., Nannenga B., Timofeev O., Donehower L.A., Anderson C.W., Appella E., Fornace A.J., Jr 2004. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat. Genet. 36:343–350 10.1038/ng1317 PubMed DOI

Castellino R.C., De Bortoli M., Lu X., Moon S.-H., Nguyen T.-A., Shepard M.A., Rao P.H., Donehower L.A., Kim J.Y. 2008. Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D. J. Neurooncol. 86:245–256 10.1007/s11060-007-9470-8 PubMed DOI PMC

Chen M.-S., Hurov J., White L.S., Woodford-Thomas T., Piwnica-Worms H. 2001. Absence of apparent phenotype in mice lacking Cdc25C protein phosphatase. Mol. Cell. Biol. 21:3853–3861 10.1128/MCB.21.12.3853-3861.2001 PubMed DOI PMC

Di Micco R., Fumagalli M., Cicalese A., Piccinin S., Gasparini P., Luise C., Schurra C., Garre’ M., Nuciforo P.G., Bensimon A., et al. 2006. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 444:638–642 10.1038/nature05327 PubMed DOI

el-Deiry W.S., Tokino T., Velculescu V.E., Levy D.B., Parsons R., Trent J.M., Lin D., Mercer W.E., Kinzler K.W., Vogelstein B. 1993. WAF1, a potential mediator of p53 tumor suppression. Cell. 75:817–825 10.1016/0092-8674(93)90500-P PubMed DOI

Fiscella M., Zhang H., Fan S., Sakaguchi K., Shen S., Mercer W.E., Vande Woude G.F., O’Connor P.M., Appella E. 1997. Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc. Natl. Acad. Sci. USA. 94:6048–6053 10.1073/pnas.94.12.6048 PubMed DOI PMC

Gorgoulis V.G., Vassiliou L.-V.F., Karakaidos P., Zacharatos P., Kotsinas A., Liloglou T., Venere M., Ditullio R.A., Jr, Kastrinakis N.G., Levy B., et al. 2005. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 434:907–913 10.1038/nature03485 PubMed DOI

Halazonetis T.D., Gorgoulis V.G., Bartek J. 2008. An oncogene-induced DNA damage model for cancer development. Science. 319:1352–1355 10.1126/science.1140735 PubMed DOI

Hollstein M., Sidransky D., Vogelstein B., Harris C.C. 1991. p53 mutations in human cancers. Science. 253:49–53 10.1126/science.1905840 PubMed DOI

Jackson S.P., Bartek J. 2009. The DNA-damage response in human biology and disease. Nature. 461:1071–1078 10.1038/nature08467 PubMed DOI PMC

Kleibl Z., Havranek O., Hlavata I., Novotny J., Sevcik J., Pohlreich P., Soucek P. 2009. The CHEK2 gene I157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population. Eur. J. Cancer. 45:618–624 10.1016/j.ejca.2008.09.022 PubMed DOI

Knudson A.G. 2002. Cancer genetics. Am. J. Med. Genet. 111:96–102 10.1002/ajmg.10320 PubMed DOI

Le Guezennec X., Bulavin D.V. 2010. WIP1 phosphatase at the crossroads of cancer and aging. Trends Biochem. Sci. 35:109–114 10.1016/j.tibs.2009.09.005 PubMed DOI

Li J., Yang Y., Peng Y., Austin R.J., van Eyndhoven W.G., Nguyen K.C.Q., Gabriele T., McCurrach M.E., Marks J.R., Hoey T., et al. 2002. Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nat. Genet. 31:133–134 10.1038/ng888 PubMed DOI

Liang C., Guo E., Lu S., Wang S., Kang C., Chang L., Liu L., Zhang G., Wu Z., Zhao Z., et al. 2012. Over-expression of wild-type p53-induced phosphatase 1 confers poor prognosis of patients with gliomas. Brain Res. 1444:65–75 10.1016/j.brainres.2011.12.052 PubMed DOI

Lindqvist A., de Bruijn M., Macurek L., Brás A., Mensinga A., Bruinsma W., Voets O., Kranenburg O., Medema R.H. 2009. Wip1 confers G2 checkpoint recovery competence by counteracting p53-dependent transcriptional repression. EMBO J. 28:3196–3206 10.1038/emboj.2009.246 PubMed DOI PMC

Lu X., Nannenga B., Donehower L.A. 2005. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev. 19:1162–1174 10.1101/gad.1291305 PubMed DOI PMC

Macůrek L., Lindqvist A., Voets O., Kool J., Vos H.R., Medema R.H. 2010. Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition. Oncogene. 29:2281–2291 10.1038/onc.2009.501 PubMed DOI

Mailand N., Falck J., Lukas C., Syljuâsen R.G., Welcker M., Bartek J., Lukas J. 2000. Rapid destruction of human Cdc25A in response to DNA damage. Science. 288:1425–1429 10.1126/science.288.5470.1425 PubMed DOI

Medema R.H., Macůrek L. 2012. Checkpoint control and cancer. Oncogene. 31:2601–2613 10.1038/onc.2011.451 PubMed DOI

Mulligan L.M., Kwok J.B.J., Healey C.S., Elsdon M.J., Eng C., Gardner E., Love D.R., Mole S.E., Moore J.K., Papi L., et al. 1993. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 363:458–460 10.1038/363458a0 PubMed DOI

Nannenga B., Lu X., Dumble M., Van Maanen M., Nguyen T.-A., Sutton R., Kumar T.R., Donehower L.A. 2006. Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice. Mol. Carcinog. 45:594–604 10.1002/mc.20195 PubMed DOI

Nguyen T.-A., Slattery S.D., Moon S.-H., Darlington Y.F., Lu X., Donehower L.A. 2010. The oncogenic phosphatase WIP1 negatively regulates nucleotide excision repair. DNA Repair (Amst.). 9:813–823 10.1016/j.dnarep.2010.04.005 PubMed DOI PMC

Nishida T., Hirota S., Taniguchi M., Hashimoto K., Isozaki K., Nakamura H., Kanakura Y., Tanaka T., Takabayashi A., Matsuda H., Kitamura Y. 1998. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat. Genet. 19:323–324 10.1038/1209 PubMed DOI

Pärssinen J., Alarmo E.-L., Karhu R., Kallioniemi A. 2008. PPM1D silencing by RNA interference inhibits proliferation and induces apoptosis in breast cancer cell lines with wild-type p53. Cancer Genet. Cytogenet. 182:33–39 10.1016/j.cancergencyto.2007.12.013 PubMed DOI

Pohlreich P., Zikan M., Stribrna J., Kleibl Z., Janatova M., Kotlas J., Zidovska J., Novotny J., Petruzelka L., Szabo C., Matous B. 2005. High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area. Breast Cancer Res. 7:R728–R736 10.1186/bcr1282 PubMed DOI PMC

Rauta J., Alarmo E.-L., Kauraniemi P., Karhu R., Kuukasjärvi T., Kallioniemi A. 2006. The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. Breast Cancer Res. Treat. 95:257–263 10.1007/s10549-005-9017-7 PubMed DOI

Ruark E., Snape K., Humburg P., Loveday C., Bajrami I., Brough R., Rodrigues D.N., Renwick A., Seal S., Ramsay E., et al. ; Breast and Ovarian Cancer Susceptibility Collaboration; Wellcome Trust Case Control Consortium 2013. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature. 493:406–410 10.1038/nature11725 PubMed DOI PMC

Saito-Ohara F., Imoto I., Inoue J., Hosoi H., Nakagawara A., Sugimoto T., Inazawa J. 2003. PPM1D is a potential target for 17q gain in neuroblastoma. Cancer Res. 63:1876–1883 PubMed

Sakaue-Sawano A., Kurokawa H., Morimura T., Hanyu A., Hama H., Osawa H., Kashiwagi S., Fukami K., Miyata T., Miyoshi H., et al. 2008. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell. 132:487–498 10.1016/j.cell.2007.12.033 PubMed DOI

Schmidt L., Duh F.-M., Chen F., Kishida T., Glenn G., Choyke P., Scherer S.W., Zhuang Z., Lubensky I., Dean M., et al. 1997. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat. Genet. 16:68–73 10.1038/ng0597-68 PubMed DOI

Ticha I., Kleibl Z., Stribrna J., Kotlas J., Zimovjanova M., Mateju M., Zikan M., Pohlreich P. 2010. Screening for genomic rearrangements in BRCA1 and BRCA2 genes in Czech high-risk breast/ovarian cancer patients: high proportion of population specific alterations in BRCA1 gene. Breast Cancer Res. Treat. 124:337–347 10.1007/s10549-010-0745-y PubMed DOI

Vogelstein B., Kinzler K.W. 2004. Cancer genes and the pathways they control. Nat. Med. 10:789–799 10.1038/nm1087 PubMed DOI

Vogelstein B., Lane D., Levine A.J. 2000. Surfing the p53 network. Nature. 408:307–310 10.1038/35042675 PubMed DOI

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