Abstract
Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of telomerase. In both mammalian tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative (ALT) recombination mechanism. In yeast, Sgs1p and its associated type IA topoisomerase, Top3p, may work coordinately in removing Holliday junction intermediates from a crossover-producing recombination pathway. Previous studies have also indicated that Sgs1 helicase acts in a telomere recombination pathway. Here we show that topoisomerase III is involved in telomere-telomere recombination. The recovery of telomere recombination-dependent survivors in a telomerase-minus yeast strain was dependent on Top3p catalytic activity. Moreover, the RIF1 and RIF2 genes are required for the establishment of TOP3/SGS1-dependent telomere-telomere recombination. In human Saos-2 ALT cells, human topoisomerase IIIalpha (hTOP3alpha) also contributes to telomere recombination. Strikingly, the telomerase activity is clearly enhanced in surviving si-hTOP3alpha Saos-2 ALT cells. Altogether, the present results suggest a potential role for hTOP3alpha in dissociating telomeric structures in telomerase-deficient cells, providing therapeutic implications in human tumors.
Highlights
Telomeres are dynamic DNA-protein complexes that protect the ends of linear chromosomes, prevent detrimental chromosome rearrangements, and defend against genomic instability and the associated risk of cancer [1,2,3]
TOP3 Contributes to Telomere Homeostasis in Wild-type and Telomerase-minus Strains—To investigate whether TOP3 contributes to telomere replication, telomere lengths in tlc1, top3, and tlc1 top3 strains were assessed by Southern blot analysis using telomeric DNA probes
TOP3 Mediates Telomerase-independent Telomere Maintenance— The above observations indicate that TOP3 is involved in telomere maintenance in yeast as well as human cells
Summary
Telomeres are dynamic DNA-protein complexes that protect the ends of linear chromosomes, prevent detrimental chromosome rearrangements, and defend against genomic instability and the associated risk of cancer [1,2,3]. Most cells in S. cerevisiae [16, 17], Kluyveromyces lactis [18], and Schizosaccharomyces pombe [19] that lack the genes for telomerase components eventually enter cell cycle arrest, survivors arise relatively frequently. In both S. cerevisiae and K. lactis, the generation of survivors requires RAD52-dependent homologous recombination. In S. cerevisiae, the majority of cells that survive in the absence of telomerase activity have multiple tandem copies of the subtelomeric YЈ element and very short terminal tracts of TG1–3/C1–3A DNA [16, 20] (type I survivors). Whether Top3p is a general mediator cooperating with the RecQ helicase to resolve recombination intermediates at telomeres is still elusive
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