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The human CST complex is a terminator of telomerase activity

Abstract

The lengths of human telomeres, which protect chromosome ends from degradation and end fusions1,2, are crucial determinants of cell lifespan3. 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 telomeres4,5 during the S phase of the cell cycle, and adds 60 nucleotides in a single round of extension6, 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 metabolism7,8,9,10,11, inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 (POT1)–TPP1 telomerase processivity factor12,13. 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.

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Figure 1: The CST complex limits telomere elongation in human cancer cells.
Figure 2: Sequence-specific binding of CST to the human telomere G-stranded sequences.
Figure 3: CST inhibits telomerase activity in vitro.
Figure 4: Cell cycle regulated telomeric association of CST.

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Acknowledgements

We thank P. Reichenbach, K. Ong and S. Feuerhahn for technical help, the PCF-EPFL core facility for protein expression and J. Cooper for discussion. Research in the laboratory of J.L. was supported by the Swiss National Science Foundation, a European Research Council advanced investigator grant (grant agreement no. 232812), the Swiss Cancer League and EPFL.

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L.-Y.C. performed most experiments, S.R. contributed to ChIP assays, L.-Y.C. and J.L. designed the study and wrote the paper.

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Correspondence to Joachim Lingner.

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The authors declare no competing financial interests.

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Chen, LY., Redon, S. & Lingner, J. The human CST complex is a terminator of telomerase activity. Nature 488, 540–544 (2012). https://doi.org/10.1038/nature11269

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