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Vol. 17, Issue 4, 1758-1767, April 2006

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Senescence of Human Fibroblasts after Psoralen Photoactivation Is Mediated by ATR Kinase and Persistent DNA Damage Foci at Telomeres

Department of Dermatology, University of Cologne, 50924 Cologne, Germany

Submitted August 1, 2005; Revised December 29, 2005; Accepted January 17, 2006
Monitoring Editor: A. Gregory Matera

Cellular senescence is a phenotype that is likely linked with aging. Recent concepts view different forms of senescence as permanently maintained DNA damage responses partially characterized by the presence of senescence-associated DNA damage foci at dysfunctional telomeres. Irradiation of primary human dermal fibroblasts with the photosensitizer 8-methoxypsoralen and ultraviolet A radiation (PUVA) induces senescence. In the present study, we demonstrate that senescence after PUVA depends on DNA interstrand cross-link (ICL) formation that activates ATR kinase. ATR is necessary for the manifestation and maintenance of the senescent phenotype, because depletion of ATR expression before PUVA prevents induction of senescence, and reduction of ATR expression in PUVA-senesced fibroblasts releases cells from growth arrest. We find an ATR-dependent phosphorylation of the histone H2AX (-H2AX). After PUVA, ATR and -H2AX colocalize in multiple nuclear foci. After several days, only few predominantly telomere-localized foci persist and telomeric DNA can be coimmunoprecipitated with ATR from PUVA-senesced fibroblasts. We thus identify ATR as a novel mediator of telomere-dependent senescence in response to ICL induced by photoactivated psoralens.

Abbreviations used: 3-CP, 3-carbethoxypsoralen; 8-MOP, 8-methoxypsoralen; ATM, Ataxia teleangiectasia mutated kinase; ATR, ATM and Rad3-related protein; CPD, cumulative population doubling; ChIP, chromatin immunoprecipitation; DDR, DNA damage response; ICL, DNA interstrand cross-links; PIKK, phosphoinositide 3-kinase related kinase; PUVA, 8-methoxypsoralen plus UVA irradiation; SDF, senescence-associated DNA damage foci; UVA, ultraviolet A radiation.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Gernot Herrmann (gernot.herrmann{at}uni-koeln.de).

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