title: A non-canonical function of topoisomerase II in disentangling dysfunctional telomeres.
abstract: The decatenation activity of topoisomerase II (Top2), which is widely conserved within the eukaryotic domain, is essential for chromosomal segregation in mitosis. It is less clear, however, whether Top2 performs the same function uniformly across the whole genome, and whether all its functions rely on decatenation. In the fission yeast, Schizosaccharomyces pombe, telomeres are bound by Taz1, which promotes smooth replication fork progression through the repetitive telomeric sequences. Hence, replication forks stall at taz1 Delta telomeres. This leads to telomeric entanglements at low temperatures (<or=20 degrees C) that cause chromosomal segregation defects and loss of viability. Here, we show that the appearance of entanglements, and the resulting cold sensitivity of taz1 Delta cells, is suppressed by mutated alleles of Top2 that confer slower catalytic turnover. This suppression does not rely on the decatenation activity of Top2. Rather, the enhanced presence of reaction intermediates in which Top2 is clamped around DNA, promotes the removal of telomeric entanglements in vivo, independently of catalytic cycle completion. We propose a model for how the clamped enzyme-DNA complex promotes proper chromosomal segregation.
authors.affiliation: Telomere Biology Laboratory, Cancer Research, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Germe
authors.forename: Kyle
authors.initials: K
authors.lastname: Miller
authors.forename: Julia Promisel
authors.initials: JP
authors.lastname: Cooper
mesh_terms: D000483:Alleles; D002384:Catalysis; D002875:Chromosomes / Q000648:ultrastructure; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry*; D019281:Dimerization; D004926:Escherichia coli / Q000378:metabolism; D007438:Introns; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000235:genetics; D016615:Telomere / Q000648:ultrastructure*; D013696:Temperature
chemical_list: D004247:DNA; D004250:DNA Topoisomerases, Type II
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