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Originally published as MBC in Press, 10.1091/mbc.E07-03-0285 on June 13, 2007 Originally published as MBC in Press, 10.1091/mbc.E07-03-0285 on May 30, 2007

Vol. 18, Issue 8, 3047-3058, August 2007

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MRX-dependent DNA Damage Response to Short Telomeres

Valeria Viscardi*, Diego Bonetti*, Hugo Cartagena-Lirola*,{dagger}, Giovanna Lucchini*, and Maria Pia Longhese*

*Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, 20126 Milan, Italy; and {dagger}Division of Hepatology and Gene Therapy, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain

Submitted March 28, 2007; Revised May 4, 2007; Accepted May 17, 2007
Monitoring Editor: Orna Cohen-Fix

Telomere structure allows cells to distinguish the natural chromosome ends from double-strand breaks (DSBs). However, DNA damage response proteins are intimately involved in telomere metabolism, suggesting that functional telomeres may be recognized as DNA damage during a time window. Here we show by two different systems that short telomeres are recognized as DSBs during the time of their replication, because they induce a transient MRX-dependent DNA damage checkpoint response during their prolonged elongation. The MRX complex, which is recruited at telomeres under these conditions, dissociates from telomeres concomitantly with checkpoint switch off when telomeres reach a new equilibrium length. We also show that MRX recruitment to telomeres is sufficient to activate the checkpoint independently of telomere elongation. We propose that MRX can signal checkpoint activation by binding to short telomeres only when they become competent for elongation. Because full-length telomeres are refractory to MRX binding and the shortest telomeres are elongated of only a few base pairs per generation, this limitation may prevent unscheduled checkpoint activation during an unperturbed S phase.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-03-0285) on May 30, 2007.

Address correspondence to: Maria Pia Longhese (mariapia.longhese{at}unimib.it).




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