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Molecular and Cellular Biology, March 2008, p. 1892-1904, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01364-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

WRN Controls Formation of Extrachromosomal Telomeric Circles and Is Required for TRF2^B-Mediated Telomere Shortening ^,

Baomin Li,¹ Sonali P. Jog,¹ Sita Reddy,^2* and Lucio Comai^1*

Department of Molecular Microbiology and Immunology,¹ Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California²

Received 30 July 2007/ Returned for modification 31 August 2007/ Accepted 8 January 2008

Telomere dysfunction has been proposed to contribute to the pathogenesis of Werner syndrome (WS), a premature-aging disorder. The WS protein WRN binds TRF2, a telomere-specific factor that protects chromosome ends. TRF2 possesses an amino-terminal domain that plays an essential role in preventing telomere shortening, as expression of TRF2^B, which lacks this domain, leads to the formation of telomeric circles, telomere shortening, and cell senescence. Our data show that the TRF2^B-induced telomeric-loop homologous-recombination pathway requires WRN helicase. In addition, we show that WRN represses the formation of spontaneous telomeric circles, as demonstrated by the increased levels of telomeric circles observed in telomerase-positive WS fibroblasts. The mechanism of circle formation in WS cells does not involve XRCC3 function. Circle formation in WS cells is reduced by reconstitution with wild-type WRN but not mutant forms lacking either exonuclease or helicase activity, demonstrating that both enzymatic activities of WRN are required to suppress telomeric-circle formation in normal cells expressing telomerase reverse transcriptase. Thus, WRN has a key protective function at telomeres which influences telomere topology and inhibits accelerated attrition of telomeres.

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* Corresponding author. Mailing address for Lucio Comai: Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, 2250 Alcazar St., CSC 264, Los Angeles, CA 90033. Phone: (323) 442-3950. Fax: (323) 442-2764. E-mail: comai{at}usc.edu. Mailing address for Sita Reddy: Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, 2250 Alcazar St., CSC 268, Los Angeles, CA 90033. Phone: (323) 442-2457. Fax: (323) 442-2764. E-mail: sitaredd{at}usc.edu

Published ahead of print on 22 January 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, March 2008, p. 1892-1904, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01364-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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