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A role for the Rb family of proteins in controlling telomere length

Nature Genetics volume 32, pages 415–419 (2002)Cite this article

Abstract

The molecular mechanisms of cellular mortality have recently begun to be unraveled. In particular, it has been discovered that cells that lack telomerase are subject to telomere attrition with each round of replication, eventually leading to loss of telomere capping function at chromosome ends1,2,3,4,5. Critically short telomeres and telomeres lacking telomere-binding proteins lose their functionality and are metabolized as DNA breaks, thus generating chromosomal fusions1,2,3,4,5,6,7,8. Telomerase activity is sufficient to rescue short telomeres and confers an unlimited proliferative capacity9,10,11. In addition, the tumor-suppressor pathway Cdkn2a/Rb1 has also been implicated as a barrier to immortalization12,13,14. Here, we report a connection between the members of the retinoblastoma family of proteins, Rb1 (retinoblastoma 1), Rbl1 (retinoblastoma-like 1) and Rbl2 (retinoblastoma-like 2), and the mechanisms that regulate telomere length. In particular, mouse embryonic fibroblasts doubly deficient in Rbl1 and Rbl2 or triply deficient in Rbl1, Rbl2 and Rb1 have markedly elongated telomeres compared with those of wildtype or Rb1-deficient cells. This deregulation of telomere length is not associated with increased telomerase activity. Notably, the abnormally elongated telomeres in doubly or triply deficient cells retain their end-capping function, as shown by the normal frequency of chromosomal fusions. These findings demonstrate a connection between the Rb1 family and the control of telomere length in mammalian cells.

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Figure 1: Deregulation of telomere length in DKO and TKO cells.
Figure 2: Abnormally elongated telomeres in DKO and TKO cells as determined by Q-FISH.
Figure 3: Greater binding of Terf1 to TKO telomeres.

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Acknowledgements

We thank T. Jacks and J. Sage for the donation of numerous vials of TKO and DKO MEFs, B. Deberman and S. Weintraub for the gift of Rb1−/− and Rb1+/+ MEFs and M. Serrano for critical reading of the manuscript and helpful discussions. M.G.-C. is a predoctoral fellow from the Spanish Ministry of Science and Technology. S.G. is supported by the US National Institutes of Health. Research at the laboratory of M.A.B. is funded by the Spanish Ministry of Science and Technology, the Regional Government of Madrid, the European Union and the Department of Immunology and Oncology (Spanish Research Council/Pharmacia Corporation).

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Authors and Affiliations

  1. Department of Immunology and Oncology, National Center of Biotechnology, Madrid, E-28049, Spain

    Marta García-Cao & María A. Blasco

  2. Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri, USA

    Susana Gonzalo & Douglas Dean

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  1. Marta García-Cao
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  2. Susana Gonzalo
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Correspondence to María A. Blasco.

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García-Cao, M., Gonzalo, S., Dean, D. et al. A role for the Rb family of proteins in controlling telomere length. Nat Genet 32, 415–419 (2002). https://doi.org/10.1038/ng1011

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