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Apoptotic DNA fragmentation factor maintains chromosome stability in a P53-independent manner

Oncogene volume 25, pages 5370–5376 (2006)Cite this article

Abstract

DNA fragmentation factor (DFF)/caspase-activated DNase (CAD) is responsible for DNA fragmentation, a hallmark event during apoptosis. Although DNA fragmentation is an evolutionarily conserved process across species, its biological function is not clearly understood. In this study, we constructed cell lines expressing a mutant ICAD (inhibitor of CAD) protein that is resistant to caspase cleavage and therefore constantly binds to DFF/CAD and inhibits DNA fragmentation. We found that irradiation of these cells led to increased chromosome aberrations and aneuploidy when compared with their parental controls. The increased chromosome instability is observed irrespective of cellular P53 status, suggesting that the effect of DFF/CAD is independent of P53. Inhibition of apoptotic DNA fragmentation resulted in increased clonogenic survival of irradiated cells and a delay in removal of cells with DNA damages induced by radiation, an effect similar to that in cells with p53 mutations. Consistent with DFF/CAD's effect on clonogenic survival, tumors established from cells deficient in DNA fragmentation showed enhanced growth in nude mice. Therefore, our results suggest that DFF/CAD plays an important and P53-independent role in maintaining chromosome stability and suppressing tumor development.

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References

  • Abel F, Sjoberg RM, Krona C, Nilsson S, Martinsson T . (2004). Int J Oncol 25: 1297–1302.

  • Abel FSR, Ejeskar K, Krona C, Martinsson T . (2002). Br J Cancer 86: 596–604.

  • Caron HvSP, de Kraker J, Bokkerink J, Egeler M, Laureys G, Slater R et al. (1996). N Engl J Med 334: 225–230.

  • Elledge SJ . (1996). Science 274: 1664–1672.

  • Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S . (1998). Nature 391: 43–50.

  • Eshleman JR, Casey G, Kochera ME, Sedwick WD, Swinler SE, Veigl ML et al. (1998). Oncogene 17: 719–725.

  • Hoyt MA, Stearns T, Botstein D . (1990). Mol Cell Biol 10: 223–234.

  • Judson HvRN, Strain L, Vandesompele J, Van Gele M, Speleman F, Bonthron DT . (2000). Hum Genet 106: 406–413.

  • Kawane K, Fukuyama H, Yoshida H, Nagase H, Ohsawa Y, Uchiyama Y et al. (2003). Nat Immunol 4: 138–144.

  • Kinsella TM, Nolan GP . (1996). Hum Gene Ther 7: 1405–1413.

  • Konishi S, Ishiguro H, Shibata Y, Kudo J, Terashita Y, Sugiura H et al. (2002). Cancer 95: 2473–2478.

  • Lechardeur D, Drzymala L, Sharma M, Zylka D, Kinach R, Pacia J et al. (2000). J Cell Biol 150: 321–334.

  • Lengauer C, Kinzler KW, Vogelstein B . (1997). Nature 386: 623–627.

  • Lengauer C, Kinzler KW, Vogelstein B . (1998). Nature 396: 643–649.

  • Li LY, Luo X, Wang X . (2001). Nature 412: 95–99.

  • Liber HL, Thilly WG . (1982). Mutat Res 94: 467–485.

  • Little JB, Nagasawa H, Keng PC, Yu Y, Li CY . (1995). J Biol Chem 270: 11033–11036.

  • Liu X, Zou H, Slaughter C, Wang X . (1997). Cell 89: 175–184.

  • Maris JM, White PS, Beltinger CP, Sulman EP, Castleberry RP, Shuster JJ et al. (1995). Cancer Res 55: 4664–4669.

  • Murray AW . (1995). Curr Opin Genet Dev 5: 5–11.

  • Nasmyth K . (1996). Trends Genet 12: 405–412.

  • Ohira M, Kageyama H, Mihara M, Furuta S, Machida T, Shishikura T et al. (2000). Oncogene 19: 4302–4307.

  • Paulovich AG, Toczyski DP, Hartwell LH . (1997). Cell 88: 315–321.

  • Sakahira H, Enari M, Nagata S . (1998). Nature 391: 96–99.

  • Schwab M, Praml C, Amler LC . (1996). Genes Chromosomes Cancer 16: 211–229.

  • Skopek TR, Liber HL, Penman BW, Thilly WG . (1978). Biochem Biophys Res Commun 84: 411–416.

  • Slane JM, Lee HS, Vorhees CV, Zhang J, Xu M . (2000). Brain Res 867: 70–79.

  • Spencer F, Gerring SL, Connelly C, Hieter P . (1990). Genetics 124: 237–249.

  • Van Gele MSF, Vandesompele J, Van Roy N, Leonard JH . (1998a). Cancer Res 58: 1503–1508.

  • Van Gele MVRN, Ronan SG, Messiaen L, Vandesompele J, Geerts ML, Naeyaert JM et al. (1998b). Genes Chromosomes Cancer 23: 67–71.

  • van Loo G, Schotte P, van Gurp M, Demol H, Hoorelbeke B, Gevaert K et al. (2001). Cell Death Differ 8: 1136–1142.

  • Yan B, Wang H, Peng Y, Hu Y, Wang H, Zhang X et al. (2006). Proc Natl Acad Sci USA 103: 1504–1509.

  • Yan B, Zemskova M, Holder S, Chin V, Kraft A, Koskinen PJ et al. (2003). J Biol Chem 278: 45358–45367.

  • Yandell DW, Little JB . (1986). Cancer Genet Cytogenet 20: 231–239.

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Acknowledgements

We thank Dr Mike Cook and Thusitha Dissanayake of Duke University for assistance in flow cytometry analysis. We thank Drs Yulin Zhao, Yuqing Yuan and Zhonghui Yang of Duke University for their helpful input to this paper. This study was supported by a grant from the US Department of Defense Prostate Cancer Research Program (DAMD17-02-1-0052), a grant from the US Department of Energy Low Dose Research Program (DE-FG02-03ER63635) and a grant from the National Aeronautics and Space Administration (NAG2-1629).

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Authors and Affiliations

  1. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA

    B Yan, D Zhuo, F Li, T Kon, M Dewhirst & C-Y Li

  2. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    H Wang

  3. West China 2nd Affiliated Hospital, Sichuan University, Chengdu, China

    H Wang

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  1. B Yan
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Correspondence to C-Y Li.

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Yan, B., Wang, H., Wang, H. et al. Apoptotic DNA fragmentation factor maintains chromosome stability in a P53-independent manner. Oncogene 25, 5370–5376 (2006). https://doi.org/10.1038/sj.onc.1209535

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