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Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas

Oncogene volume 29, pages 1720–1731 (2010)Cite this article

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Abstract

The tumor suppressive activities of the Kip-family of cyclin-dependent kinase (cdk) inhibitors often go beyond their role directly regulating the cell cycle. In this study, we show that p27 enhances Rad51 accumulation during repair of double-strand DNA breaks. Progression of platelet-derived growth factor (PDGF)-induced oligodendrogliomas was accelerated in mice lacking the cyclin–cdk binding activities of p27kip1. To understand how p27 deficiency contributes, cell lines were developed from RCAS–PDGF infection of nestin-tv-a brain progenitor cells in culture. p27 deficiency did not affect cell proliferation in early passage cell lines; however, the absence of p27 affected chromosomal stability. In p27-deficient cells, the activation of Atm and Chk2 and the accumulation of γ-H2AX was unaffected when compared with wild-type cells, and the number of phospho-histone H3 staining mitotic cells was decreased, consistent with G2/M checkpoint activation. However, the percentage of Rad51 foci-positive cells was decreased, and the kinase activity that targets the C-terminus of BRCA2, regulating BRCA2/Rad51 interactions, was increased in lysates derived from p27-deficient cells. Increased numbers of chromatid breaks in p27-deficient cells that adapted to the checkpoint were also observed. These findings suggest that Rad51-dependent repair of double-stranded breaks was hindered in p27-deficient cells, leading to chromosomal instability, a hallmark of cancers with poor prognosis.

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Acknowledgements

We thank Travis Stracker, John Petrini, Yossi Shiloh, Yuhui Liu, Nancy Yeh, Daniel Ciznadija, Dolores Hambardzumyan, Oren Becher, Elena Fomchenko, and Robert Finney, Katia Manova, Lei Zhang, Kalyani Chadalavada, Margaret Leversha, Jan Hendrix and Diane Domingo. This research was supported by the US National Institutes of Health Grant CA96582 (to MR, AK and EH), CA89563 (to AK) and funds from The Golfers Against Cancer Foundation (to AK). Additional support was provided by an Institutional Core Grant to Memorial Sloan-Kettering Cancer Center.

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Authors and Affiliations

  1. Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    W L See & M D Resh

  2. Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    J P Miller & A Koff

  3. Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    M Squatrito & E Holland

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  1. W L See
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Correspondence to M D Resh.

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See, W., Miller, J., Squatrito, M. et al. Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas. Oncogene 29, 1720–1731 (2010). https://doi.org/10.1038/onc.2009.465

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