The human CST complex is a terminator of telomerase activity

Nature. 2012 Aug 23;488(7412):540-4. doi: 10.1038/nature11269.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / metabolism
  • Base Sequence
  • Cell Line, Tumor
  • DNA / genetics
  • DNA / metabolism
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • Electrophoretic Mobility Shift Assay
  • Enzyme Assays
  • G2 Phase
  • HEK293 Cells
  • Humans
  • Longevity
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Protein Binding
  • S Phase
  • Serine Proteases / metabolism
  • Telomerase / antagonists & inhibitors*
  • Telomerase / metabolism
  • Telomere / genetics
  • Telomere / metabolism
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*

Substances

  • Ctc1 protein, human
  • Multiprotein Complexes
  • POT1 protein, human
  • Stn1 protein, human
  • Telomere-Binding Proteins
  • Ten1 protein, human
  • DNA
  • Telomerase
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 1