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Mol. Cell. Biol. doi:10.1128/MCB.01364-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

WRN controls formation of extrachromosomal telomeric circles and is required for TRF2^B-mediated telomere shortening

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

^* To whom correspondence should be addressed. Email: sitaredd{at}usc.edu. comai{at}usc.edu.

	Abstract

Telomere dysfunction has been proposed to contribute to the pathogenesis of Werner syndrome, a premature aging disorder. The Werner syndrome 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 t-loop HR pathway requires WRN helicase. In addition, we show that WRN represses formation of spontaneous telomeric circles, as demonstrated by the increased levels of telomeric circles observed in telomerase-positive Werner syndrome fibroblasts. The mechanism of circle formation in WS cells does not involve XRCC3 function. Circle formation in Werner syndrome cells is reduced by reconstitution with wild-type but not mutants WRN lacking either exonuclease or helicase activity, demonstrating that both enzymatic activities of WRN activities are required to suppress telomeric circles formation in normal cells expressing TERT. Thus, WRN has a key protective function at telomeres which influences telomere topology and inhibits accelerated attrition of telomeres.

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