title: The human CST complex is a terminator of telomerase activity.
abstract: The lengths of human telomeres, which protect chromosome ends from degradation and end fusions, are crucial determinants of cell lifespan. During embryogenesis and in cancer, the telomerase enzyme counteracts telomeric DNA shortening. As shown in cancer cells, human telomerase binds the shelterin component TPP1 at telomeres during the S phase of the cell cycle, and adds ~60 nucleotides in a single round of extension, after which telomerase is turned off by unknown mechanisms. Here we show that the human CST (CTC1, STN1 and TEN1) complex, previously implicated in telomere protection and DNA metabolism, inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 (POT1)–TPP1 telomerase processivity factor. CST competes with POT1–TPP1 for telomeric DNA, and CST–telomeric-DNA binding increases during late S/G2 phase only on telomerase action, coinciding with telomerase shut-off. Depletion of CST allows excessive telomerase activity, promoting telomere elongation. We propose that through binding of the telomerase-extended telomere, CST limits telomerase action at individual telomeres to approximately one binding and extension event per cell cycle. Our findings define the sequence of events that occur to first enable and then terminate telomerase-mediated telomere elongation.
authors: Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne, Station 19, 1015 Lausanne, Switzerland.
authors: Liuh-Yow
authors: LY
authors: Chen
authors: Sophie
authors: S
authors: Redon
authors: Joachim
authors: J
authors: Lingner
mesh_terms: D045744:Cell Line, Tumor; D057075:Enzyme Assays; D016195:G2 Phase; D057809:HEK293 Cells; D006801:Humans; D008136:Longevity; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016196:S Phase; D000089804:Shelterin Complex; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C495876:ACD protein, human; C544945:Ctc1 protein, human; D046912:Multiprotein Complexes; C440849:POT1 protein, human; D000089804:Shelterin Complex; C544946:Stn1 protein, human; D034501:Telomere-Binding Proteins; C544947:Ten1 protein, human; D019098:Telomerase