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 Posted: Tue Oct 07, 2008 8:38 pm Post subject: Rapid regulation of telomere length is mediated by poly(ADP- |
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Nucleic Acids Res. 2008 Oct 3. [Epub ahead of print]
Rapid regulation of telomere length is mediated by poly(ADP-ribose)
polymerase-1.Beneke S, Cohausz O, Malanga M, Boukamp P, Althaus F,
Bürkle A.
Molecular Toxicology Group, Department of Biology, University of
Konstanz, 78457 Konstanz, Germany, Department Genetics of Skin
Carcinogenesis, German Cancer Research Center, Im Neuenheimer Feld
280, 69120 Heidelberg, Germany, Institute of Veterinary Pharmacology
and Toxicology, University of Zurich/Vetsuisse faculty,
Winterthurerstrasse 260, 8057 Zurich, Switzerland and Department of
Structural and Functional Biology, University Federico II of Naples,
Via Cinthia, Monte S. Angelo, 80126 Naples, Italy.
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.
PMID: 18835851 [PubMed - as supplied by publisher] |
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