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Molecular and Cellular Biology, March 2009, p. 1608-1625, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01339-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

TRF1 Controls Telomere Length and Mitotic Fidelity in Epithelial Homeostasis{triangledown} ,{dagger}

Purificacion Muñoz ,1,{ddagger},§ Raquel Blanco,1,{ddagger} Guillermo de Carcer,2 Stefan Schoeftner,1 Roberta Benetti,1,¶ Juana M. Flores,3 Marcos Malumbres,2 and Maria A. Blasco1*

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain,1 Cell Division and Cancer Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain,2 Animal Surgery and Medicine Department, Facultad de Veterinaria, Universidad Complutense de Madrid, 28029 Madrid, Spain3

Received 22 August 2008/ Returned for modification 20 October 2008/ Accepted 26 December 2008

TRF1 is a component of the shelterin complex at mammalian telomeres; however, a role for TRF1 in telomere biology in the context of the organism is unclear. In this study, we generated mice with transgenic TRF1 expression targeted to epithelial tissues (K5TRF1 mice). K5TRF1 mice have shorter telomeres in the epidermis than wild-type controls do, and these are rescued in the absence of the XPF nuclease, indicating that TRF1 acts as a negative regulator of telomere length by controlling XPF activity at telomeres, similar to what was previously described for TRF2-overexpressing mice (K5TRF2 mice). K5TRF1 cells also show increased end-to-end chromosomal fusions, multitelomeric signals, and increased telomere recombination, indicating an impact of TRF1 on telomere integrity, again similar to the case in K5TRF2 cells. Intriguingly, K5TRF1 cells, but not K5TRF2 cells, show increased mitotic spindle aberrations. TRF1 colocalizes with the spindle assembly checkpoint proteins BubR1 and Mad2 at mouse telomeres, indicating a link between telomeres and the mitotic spindle. Together, these results demonstrate that TRF1, like TRF2, negatively regulates telomere length in vivo by controlling the action of the XPF nuclease at telomeres; in addition, TRF1 has a unique role in the mitotic spindle checkpoint.

* Corresponding author. Mailing address: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain. Phone: 34 917328031. Fax: 34 917328028. E-mail: mblasco{at}cnio.es

{triangledown} Published ahead of print on 5 January 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} P.M. and R.B. contributed equally to this work.

§ Present address: Epigenetics and Cancer Biology Program (PEBC), Catalan Institute of Oncology (ICO), Gran Via s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.

Present address: Laboratorio Nazionale Centro Universitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, 34012 Trieste, Italy.

Molecular and Cellular Biology, March 2009, p. 1608-1625, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01339-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Oganesian, L., Karlseder, J. (2009). Telomeric armor: the layers of end protection. J. Cell Sci. 122: 4013-4025 [Abstract] [Full Text]  
  • Martinez, P., Thanasoula, M., Munoz, P., Liao, C., Tejera, A., McNees, C., Flores, J. M., Fernandez-Capetillo, O., Tarsounas, M., Blasco, M. A. (2009). Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 23: 2060-2075 [Abstract] [Full Text]  


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