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J. Biol. Chem., Vol. 281, Issue 52, 40503-40514, December 29, 2006

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Telomerase-independent Regulation of ATR by Human Telomerase RNA^*

From the Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands

The human telomerase RNA (hTR), together with the telomerase reverse transcriptase, hTERT, constitute the core components of telomerase that is essential for telomere maintenance. While hTR is ubiquitously expressed, hTERT is normally restricted to germ cells and certain stem cells, but both are often deregulated during tumorigenesis. Here, we investigated the effects of changes in hTR cellular levels. Surprisingly, while inhibition of hTR expression triggers a rapid, telomerase-independent, growth arrest associated with p53 and CHK1 activation, its increased expression neutralizes activation of these pathways in response to genotoxic stress. These hTR effects are mediated through ATR and are sufficiently strong to impair ATR-mediated DNA-damage checkpoint responses. Furthermore, in response to low UV radiation, which activates ATR, endogenous hTR levels increase irrespective of telomerase status. Thus, we uncovered a novel, telomerase-independent, function of hTR that restrains ATR activity and participates in the recovery of cells from UV radiation.

Received for publication, August 11, 2006 , and in revised form, November 6, 2006.

^* This work was supported by grants from the Dutch Cancer Society (Koningin Wilhelmina Fonds) (to M. K. and R. A.) and by a EURYI award (to R. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S10.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. Tel.: 31-20-512-2079; Fax: 31-20-512-2029; E-mail: r.agami{at}nki.nl

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