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J. Biol. Chem., Vol. 280, Issue 7, 5249-5257, February 18, 2005

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Expression of a RecQ Helicase Homolog Affects Progression through Crisis in Fission Yeast Lacking Telomerase^*

Jeffrey G. Mandell, Karen J. Goodrich, Jürg Bähler¶, and Thomas R. Cech||

From the Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0215 and ^¶The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom

RecQ helicases play roles in telomere maintenance in cancerous human cells using the alternative lengthening of telomeres mechanism and in budding yeast lacking telomerase. Fission yeast lacking the catalytic subunit of telomerase (trt1⁺) up-regulate the expression of a previously uncharacterized sub-telomeric open reading frame as survivors emerge from crisis. Here we show that this open reading frame encodes a protein with homology to RecQ helicases such as the human Bloom's and Werner's syndrome proteins and that copies of the helicase gene are present on multiple chromosome ends. Characterization of the helicase transcript revealed a 7.6-kilobase RNA that was associated with polyribosomes, suggesting it is translated. A 3.6-kilobase domain of the helicase gene predicted to encode the region with catalytic activity was cloned, and both native and mutant forms of this domain were overexpressed in trt1^– cells as they progressed through crisis. Overexpression of the native form caused cells to recover from crisis earlier than cells with a vector-only control, whereas overexpression of the mutant form caused delayed recovery from crisis. Taken together, the sequence homology, functional analysis, and site-directed mutagenesis indicate that the protein is likely a second fission yeast RecQ helicase (in addition to Rqh1) that participates in telomere metabolism during crisis. These results strengthen the notion that in multiple organisms RecQ helicases contribute to survival after telomere damage.

Received for publication, November 11, 2004 , and in revised form, December 8, 2004.

^* This work was supported by National Institutes of Health Grant GM28039. 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 nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) BK005597.

Supported by Damon Runyon Cancer Research Foundation Post-doctoral Fellowship DRG 1617.

^|| To whom correspondence should be addressed. Tel.: 303-492-8606; Fax: 303-492-6194; E-mail: thomas.cech{at}colorado.edu.

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