Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation

Oncogene volume 25, pages 746–755 (2006)Cite this article

Abstract

Although it is unclear which cellular factor(s) is responsible for the genetic instability associated with initiating and sustaining cell transformation, it is known that many cancers have mutations that inactivate the Rb-mediated proliferation pathway. We show here that pRb inactivation and the resultant deregulation of one E2F family member, E2F1, leads to DNA double-strand break (DSB) accumulation in normal diploid human cells. These DSBs occur independent of Atm, p53, caspases, reactive oxygen species, and apoptosis. Moreover, E2F1 does not contribute to c-Myc-associated DSBs, indicating that the DSBs associated with these oncoproteins arise through distinct pathways. We also find E2F1-associated DSBs in an Rb mutated cancer cell line in the absence of an exogenous DSB stimulus. These basal, E2F1-associated DSBs are not observed in a p16ink4a inactivated cancer cell line that retains functional pRb, unless pRb is depleted. Thus, Rb status is key to regulating both the proliferation promoting functions associated with E2F and for preventing DNA damage accumulation if E2F1 becomes deregulated. Taken together, these data suggest that loss of Rb creates strong selective pressure, via DSB accumulation, for inactivating p53 mutations and that E2F1 contributes to the genetic instability associated with transformation and tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K et al. (2005). Nature 434: 864–870.

  • Berkovich E, Ginsberg D . (2003). Oncogene 22: 161–167.

  • Biroccio A, Benassi B, Amodei S, Gabellini C, Del Bufalo D, Zupi G . (2001). Mol Pharmacol 60: 174–182.

  • Bosco EE . (2004). Nucleic Acids Res 32: 25–34.

  • DeGregori J, Leone G, Miron A, Jakoi L, Nevins JR . (1997). Proc Natl Acad Sci USA 94: 7245–7250.

  • Duensing S, Munger K . (2002). Cancer Res 62: 7075–7082.

  • Dyson N . (1998). Genes Dev 12: 2245–2262.

  • Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T et al. (2005). Nature 434: 907–913.

  • Johnson DG, Schwarz JK, Cress WD, Nevins JR . (1993). Nature 365: 349–352.

  • Kowalik TF, DeGregori J, Schwarz JK, Nevins JR . (1995). J Virol 69: 2491–2500.

  • Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH et al. (2001). Mol Cell 8: 105–113.

  • Lomazzi M, Moroni MC, Jensen MR, Frittoli E, Helin K . (2002). Nat Genet 31: 190–194.

  • Matsumura I, Tanaka H, Kanakura Y . (2003). Cell Cycle 2: 333–338.

  • Morgenbesser SD, Williams BO, Jacks T, DePinho RA . (1994). Nature 371: 72–74.

  • Nevins JR . (2001). Hum Mol Genet 10: 699–703.

  • Olive PL, Wlodek D, Banath JP . (1991). Cancer Res 51: 4671–4676.

  • Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM . (2000). Curr Biol 10: 886–895.

  • Powers JT, Hong S, Mayhew CN, Rogers PM, Knudsen ES, Johnson DG . (2004). Mol Cancer Res 2: 203–214.

  • Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM . (1998). J Biol Chem 273: 5858–5868.

  • Rogoff HA, Pickering MT, Frame FM, Debatis ME, Sanchez Y, Jones S et al. (2004). Mol Cell Biol 24: 2968–2977.

  • Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S . (2004). Annu Rev Biochem 73: 39–85.

  • Schwarz JK, Bassing CH, Kovesdi I, Datto MB, Blazing M, George S et al. (1995). Proc Natl Acad Sci USA 92: 483–487.

  • Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR . (2000). Genes Dev 14: 2501–2514.

  • Tanaka H, Matsumura I, Ezoe S, Satoh Y, Sakamaki T, Albanese C et al. (2002). Mol Cell 9: 1017–1029.

  • Tominaga K, Morisaki H, Kaneko Y, Fujimoto A, Tanaka T, Ohtsubo M et al. (1999). J Biol Chem 274: 31463–31467.

  • Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM et al. (2002). Mol Cell 9: 1031–1044.

  • White AE, Livanos EM, Tlsty TD . (1994). Genes Dev 8: 666–677.

Download references

Acknowledgements

We thank Rachel Gerstein, Kendall Knight, Dario Altieri, Steve Grossman, Nick Rhind, and Kowalik lab members for commenting on the manuscript. This work was supported by National Institutes of Health (NIH) Grant CA86038 (TFK).

The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, UMass Cancer Center, University of Massachusetts Medical School, Worcester, MA, USA

    M T Pickering & T F Kowalik

Authors
  1. M T Pickering
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T F Kowalik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T F Kowalik.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pickering, M., Kowalik, T. Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation. Oncogene 25, 746–755 (2006). https://doi.org/10.1038/sj.onc.1209103

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209103

Keywords

This article is cited by

Search

Advanced search

Quick links