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Small molecule–based reversible reprogramming of cellular lifespan

A Retraction to this article was published on 01 July 2008

A Corrigendum to this article was published on 01 February 2007

This article has been updated


Most somatic cells encounter an inevitable destiny, senescence1,2. Little progress has been made in identifying small molecules that extend the finite lifespan of normal human cells. Here we show that the intrinsic 'senescence clock' can be reset in a reversible manner by selective modulation of the ataxia telangiectasia–mutated (ATM) protein and ATM- and Rad3-related (ATR) protein with a small molecule, CGK733. This compound was identified by a high-throughput phenotypic screen with automated imaging. Employing a magnetic nanoprobe technology, magnetism-based interaction capture (MAGIC)3, we identified ATM as the molecular target of CGK733 from a genome-wide screen. CGK733 inhibits ATM and ATR kinase activities and blocks their checkpoint signaling pathways with great selectivity. Consistently, siRNA-mediated knockdown of ATM and ATR induced the proliferation of senescent cells, although with lesser efficiency than CGK733. These results might reflect the specific targeting of the kinase activities of ATM and ATR by CGK733 without affecting any other domains required for cell proliferation.

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Figure 1: Identification of a small molecule that reverses senescence.
Figure 2: Molecular target identification based on MAGIC technology.
Figure 3: Effects of CGK733 on ATM and ATR and related kinase signaling pathways.
Figure 4: Effects of CGK733 on kinase signaling pathways related to ATM and ATR.

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  • 22 December 2006

    In the version of this article initially published, no competing financial interests were declared. The authors now declare that they have competing interests that might be perceived to influence the results and discussion reported in this paper, which are detailed in a declaration of competing financial interests accompanying the article. The error has been corrected in the HTML and PDF versions of the article.


  1. Wright, W.E. & Shay, J.W. Historical claims and current interpretations of replicative aging. Nat. Biotechnol. 20, 682–688 (2002).

    Article  CAS  Google Scholar 

  2. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

    Article  CAS  Google Scholar 

  3. Won, J. et al. A magnetic nanoprobe technology for detecting molecular interactions in live cells. Science 309, 121–125 (2005).

    Article  CAS  Google Scholar 

  4. Jacobs, J.J. et al. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers. Nat. Genet. 26, 291–299 (2000).

    Article  CAS  Google Scholar 

  5. Gil, J., Bernard, D., Martinez, D. & Beach, D. Polycomb CBX7 has a unifying role in cellular lifespan. Nat. Cell Biol. 6, 67–72 (2004).

    Article  CAS  Google Scholar 

  6. Bodnar, A.G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998).

    Article  CAS  Google Scholar 

  7. Crews, C.M. & Splittgerber, U. Chemical genetics: exploring and controlling cellular processes with chemical probes. Trends Biochem. Sci. 24, 317–320 (1999).

    Article  CAS  Google Scholar 

  8. Schreiber, S.L. Small molecules: the missing link in the central dogma. Nat. Chem. Biol. 1, 64–66 (2005).

    Article  CAS  Google Scholar 

  9. van Steensel, B., Smogorzewska, A. & de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401–413 (1998).

    Article  CAS  Google Scholar 

  10. Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003).

    Article  CAS  Google Scholar 

  11. Stockwell, B.R. Exploring biology with small organic molecules. Nature 432, 846–854 (2004).

    Article  CAS  Google Scholar 

  12. Burdine, L. & Kodadek, T. Target identification in chemical genetics: the (often) missing link. Chem. Biol. 11, 593–597 (2004).

    Article  CAS  Google Scholar 

  13. Cohen, P. Protein kinases—the major drug targets of the twenty-first century? Nat. Rev. Drug Discov. 1, 309–315 (2002).

    Article  CAS  Google Scholar 

  14. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168 (2003).

    Article  CAS  Google Scholar 

  15. Kastan, M.B. & Bartek, J. Cell cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    Article  CAS  Google Scholar 

  16. Bode, A.M. & Dong, Z. Post-translational modification of p53 in tumorigenesis. Nat. Rev. Cancer 4, 793–805 (2004).

    Article  CAS  Google Scholar 

  17. Zimber, A., Nguyen, Q.D. & Gespach, C. Nuclear bodies and compartments: functional roles and cellular signalling in health and disease. Cell. Signal. 16, 1085–1104 (2004).

    Article  CAS  Google Scholar 

  18. Vivanco, I. & Sawyers, C.L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002).

    Article  CAS  Google Scholar 

  19. Tresini, M., Mawal-dewan, M., Cristofalo, V.J. & Sell, C. A phosphatidylinositol 3-kinase inhibitor induces a senescent-like growth arrest in human diploid fibroblast cells. Cancer Res. 58, 1–4 (1998).

    CAS  PubMed  Google Scholar 

  20. Sarbassov, D.D., Guertin, D.A., Ali, S.M. & Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science 307, 1098–1101 (2005).

    Article  CAS  Google Scholar 

  21. Herbig, U., Jobling, W., Chen, B.P.C., Chen, D.J. & Sedivy, J.M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell 14, 501–513 (2004).

    Article  CAS  Google Scholar 

  22. Ben-Porath, I. & Weinberg, R.A. The signals and pathways activating cellular senescence. Int. J. Biochem. Cell Biol. 37, 961–976 (2005).

    Article  CAS  Google Scholar 

  23. Karlseder, J., Broccoli, D., Dai, Y., Hardy, S. & de Lange, T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321–1325 (1999).

    Article  CAS  Google Scholar 

  24. d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    Article  CAS  Google Scholar 

  25. Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004).

    Article  CAS  Google Scholar 

  26. Pandita, T.K. ATM function and telomere stability. Oncogene 21, 611–618 (2002).

    Article  CAS  Google Scholar 

  27. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

    Article  CAS  Google Scholar 

  28. Brown, E.J. & Baltimore, D. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17, 615–628 (2003).

    Article  CAS  Google Scholar 

  29. Shechter, D., Costanzo, V. & Gautier, J. ATR and ATM regulate the timing of DNA replication origin firing. Nat. Cell Biol. 6, 648–655 (2004).

    Article  CAS  Google Scholar 

  30. Dimri, G.P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  Google Scholar 

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We thank T. de Lange, R.Y. Tsien, J. Campisi, J. Chung, G.P. Nolan, M.R. Stampfer and D.S. Lim for gifts of reagents. This work was supported by CGK Co. Ltd. and was also partially supported by the Korea Research Foundation grant (KRF-2005-C00097), the Korea Health 21 R&D Project (A040042) and the Chemical Genomics program from the Korean Ministry of Science and Technology.

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Correspondence to Tae Kook Kim.

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Competing interests

T.K.K. receives support for research programs from CGK Co., Ltd. M.K. has a part-time consulting relationship with CGK Co., Ltd.*

*Note: In the version of this article initially published, no competing financial interests were declared. The authors now declare that they have competing interests that might be perceived to influence the results and discussion reported in this paper, which are detailed in a declaration of competing financial interests accompanying the article. The error has been corrected in the HTML and PDF versions of the article.

Supplementary information

Supplementary Fig. 1

Establishment of cellular senescence by overexpression of TRF2ΔBΔM. (PDF 35 kb)

Supplementary Fig. 2

Reversal of replicative senescence of BJ and HMEC cells by CGK733. (PDF 160 kb)

Supplementary Fig. 3

Karyotypes of the senescent cells induced to proliferate by CGK733. (PDF 7 kb)

Supplementary Fig. 4

Effects of CGK733 on ATM and ATR kinase activities inside cells. (PDF 63 kb)

Supplementary Fig. 5

Effects of ATM/ATR siRNAs and CGK733 on the proliferation of senescent cells. (PDF 8 kb)

Supplementary Fig. 6

Synthesis of KU-55933 and a CGK733-biotin derivative. (PDF 26 kb)

Supplementary Fig. 7

Effects of KU-55933 on replicative senescence. (PDF 7 kb)

Supplementary Methods (PDF 128 kb)

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Won, J., Kim, M., Kim, N. et al. Small molecule–based reversible reprogramming of cellular lifespan. Nat Chem Biol 2, 369–374 (2006).

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