title: Deregulated telomere transcription causes replication-dependent telomere shortening and promotes cellular senescence.
abstract: Telomeres are transcribed into non-coding TElomeric Repeat containing RNAs (TERRA). We have employed a transcriptionally inducible telomere to investigate how telomere transcription affects telomere function in Saccharomyces cerevisiae. We report that telomere shortening resulting from high levels of telomere transcription stems from a DNA replication-dependent loss of telomere tracts, which can occur independent of both telomerase inhibition and homologous recombination. We show that in order for telomere loss to occur, transcription must pass through the telomere tract itself producing a TERRA molecule. We demonstrate that increased telomere transcription of a single telomere leads to a premature cellular senescence in the absence of a telomere maintenance mechanism (telomerase and homology directed repair). Similar rapid senescence and telomere shortening are also seen in sir2Δ cells with compromised telomere maintenance, where TERRA levels are increased at natural telomeres. These data suggest that telomere transcription must be tightly controlled to prevent telomere loss and early onset senescence.
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Maicher
authors.forename: Lisa
authors.initials: L
authors.lastname: Kastner
authors.forename: Martina
authors.initials: M
authors.lastname: Dees
authors.forename: Brian
authors.initials: B
authors.lastname: Luke
mesh_terms: D016922:Cellular Senescence; D004261:DNA Replication; D017353:Gene Deletion; D012091:Repetitive Sequences, Nucleic Acid; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics; D056565:Sirtuin 2 / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D059506:Telomere Shortening; D014158:Transcription, Genetic
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C509185:EST2 protein, S cerevisiae; D019098:Telomerase; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2