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J. Biol. Chem., Vol. 280, Issue 11, 10840-10845, March 18, 2005

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Amplification of Telomeric Arrays via Rolling-circle Mechanism^*

Jozef Nosek, Adriana Rycovska, Alexander M. Makhov, Jack D. Griffith¶, and Lubomir Tomaska||**

From the Department of Biochemistry, Mlynska dolina CH-1, and the ^||Department of Genetics, Mlynska dolina B-1, Faculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovakia and Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599

Alternative (telomerase-independent) lengthening of telomeres mediated through homologous recombination is often accompanied by a generation of extrachromosomal telomeric circles (t-circles), whose role in direct promotion of recombinational telomere elongation has been recently demonstrated. Here we present evidence that t-circles in a natural telomerase-deficient system of mitochondria of the yeast Candida parapsilosis replicate independently of the linear chromosome via a rolling-circle mechanism. This is supported by an observation of (i) single-stranded DNA consisting of concatameric arrays of telomeric sequence, (ii) lasso-shaped molecules representing rolling-circle intermediates, and (iii) preferential incorporation of deoxyribonucleotides into telomeric fragments and t-circles. Analysis of naturally occurring variant t-circles revealed conserved motifs with potential function in driving the rolling-circle replication. These data indicate that extrachromosomal t-circles observed in a wide variety of organisms, including yeasts, plants, Xenopus laevis, and certain human cell lines, may represent independent replicons generating telomeric sequences and, thus, actively participating in telomere dynamics. Moreover, because of the promiscuous occurrence of t-circles across phyla, the results from yeast mitochondria have implications related to the primordial system of telomere maintenance, providing a paradigm for evolution of telomeres in nuclei of early eukaryotes.

Received for publication, August 13, 2004 , and in revised form, December 17, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AY468377, AY468378, and AY468379.

^* This work was supported in part by grants from the Fogarty International Research Collaboration (1-R03-TW05654-01), Howard Hughes Medical Institute (55000327), and the Slovak grant agencies VEGA (1/2331/05 and 1/0006/03) and APVT (20–003902). 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.

^¶ Supported by an Ellison Senior Scholar Award and National Institutes of Health Grant GM31819.

^** To whom correspondence should be addressed. Tel.: 421-2-60296-536; Fax: 421-2-60296-452; E-mail: tomaska{at}fns.uniba.sk.

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