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Molecular and Cellular Biology, May 2002, p. 3474-3487, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3474-3487.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Targeting Assay To Study the cis Functions of Human Telomeric Proteins: Evidence for Inhibition of Telomerase by TRF1 and for Activation of Telomere Degradation by TRF2

Katia Ancelin,1,{dagger} Michele Brunori,1 Serge Bauwens,1 Catherine-Elaine Koering,1 Christine Brun,1,{ddagger} Michelle Ricoul,2 Jean-Patrick Pommier,2 Laure Sabatier,2 and Eric Gilson1*

Laboratoire de Biologie Moléculaire et Cellulaire, UMR5665 CNRS/ENSL, Ecole Normale Supérieure de Lyon, Lyon,1 CEA, DSV/DRR Commissariat à l'Energie Atomique, Laboratoire de Radiobiologie et Oncologie, Fontenay-aux-Roses, France2

Received 17 December 2001/ Returned for modification 4 February 2002/ Accepted 16 February 2002

We investigated the control of telomere length by the human telomeric proteins TRF1 and TRF2. To this end, we established telomerase-positive cell lines in which the targeting of these telomeric proteins to specific telomeres could be induced. We demonstrate that their targeting leads to telomere shortening. This indicates that these proteins act in cis to repress telomere elongation. Inhibition of telomerase activity by a modified oligonucleotide did not further increase the pace of telomere erosion caused by TRF1 targeting, suggesting that telomerase itself is the target of TRF1 regulation. In contrast, TRF2 targeting and telomerase inhibition have additive effects. The possibility that TRF2 can activate a telomeric degradation pathway was directly tested in human primary cells that do not express telomerase. In these cells, overexpression of full-length TRF2 leads to an increased rate of telomere shortening.

* Corresponding author. Mailing address: Laboratoire de Biologie Moléculaire et Cellulaire, UMR5665 CNRS/ENSL, Ecole Normale Supérieure de Lyon, Lyon, France. Phone: 33 472 72 84 53. Fax: 33 472 72 80 80. E-mail: Eric.Gilson{at}ens-lyon.fr.

{dagger} Present address: Surani Group, Wellcome/Cancer Research, Institute of Cancer and Developmental Biology, Cambridge CB2 1QR, United Kingdom.

{ddagger} Present address: Laboratoire de Génétique et Physiologie du Développement, Institut de Biologie du Développement de Marseille, Parc Technologique et Scientifique de Luminy, 13288 Marseille Cedex 9, France.

Molecular and Cellular Biology, May 2002, p. 3474-3487, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3474-3487.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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