Nucleic Acids Research Advance Access originally published online on October 3, 2008
Nucleic Acids Research 2008 36(19):6309-6317; doi:10.1093/nar/gkn615
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nucleic Acids Research, 2008, Vol. 36, No. 19 6309-6317
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Rapid regulation of telomere length is mediated by poly(ADP-ribose) polymerase-1
1Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany, 2Department Genetics of Skin Carcinogenesis, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, 3Institute of Veterinary Pharmacology and Toxicology, University of Zurich/Vetsuisse faculty, Winterthurerstrasse 260, 8057 Zurich, Switzerland and 4Department of Structural and Functional Biology, University Federico II of Naples, Via Cinthia, Monte S. Angelo, 80126 Naples, Italy
*To whom correspondence should be addressed. Tel: +49 7531 884067; Fax: +49 7531 884033; Email: sascha.beneke{at}uni-konstanz.de
Correspondence may also be addressed to Alexander Bürkle. Tel: +49 7531 884035; Fax: +49 7531 884033; Email: alexander.buerkle{at}uni-konstanz.de
Received June 30, 2008. Revised August 25, 2008. Accepted September 10, 2008.
Shelterin/telosome is a multi-protein complex at mammalian telomeres, anchored to the double-stranded region by the telomeric-repeat binding factors-1 and -2. In vitro modification of these proteins by poly(ADP-ribosyl)ation through poly(ADP-ribose) polymerases-5 (tankyrases) and -1/-2, respectively, impairs binding. Thereafter, at least telomeric-repeat binding factor-1 is degraded by the proteasome. We show that pharmacological inhibition of poly(ADP-ribose) polymerase activity in cells from two different species leads to rapid decrease in median telomere length and stabilization at a lower setting. Specific knockdown of poly(ADP-ribose) polymerase-1 by RNA interference had the same effect. The length of the single-stranded telomeric overhang as well as telomerase activity were not affected. Release of inhibition led to a fast re-gain in telomere length to control levels in cells expressing active telomerase. We conclude that poly(ADP-ribose) polymerase-1 activity and probably its interplay with telomeric-repeat binding factor-2 is an important determinant in telomere regulation. Our findings reinforce the link between poly(ADP-ribosyl)ation and aging/longevity and also impact on the use of poly(ADP-ribose) polymerase inhibitors in tumor therapy.