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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Nature Open Access 13 July 2022
Nature Communications Open Access 05 November 2021
Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres
Nature Communications Open Access 17 September 2021
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Jain, D. & Cooper, J. P. Telomeric strategies: means to an end. Annu. Rev. Genet. 44, 243–269 (2010)
de Lange, T. How telomeres solve the end-protection problem. Science 326, 948–952 (2009)
Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998)
Abreu, E. et al. TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol. Cell. Biol. 30, 2971–2982 (2010)
Xin, H. et al. TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase. Nature 445, 559–562 (2007)
Zhao, Y. et al. Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions. Mol. Cell 42, 297–307 (2011)
Miyake, Y. et al. RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol. Cell 36, 193–206 (2009)
Casteel, D. E. et al. A DNA polymerase-α·primase cofactor with homology to replication protein A-32 regulates DNA replication in mammalian cells. J. Biol. Chem. 284, 5807–5818 (2009)
Surovtseva, Y. V. et al. Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes. Mol. Cell 36, 207–218 (2009)
Nakaoka, H., Nishiyama, A., Saito, M. & Ishikawa, F. Xenopus laevis Ctc1-Stn1-Ten1 (xCST) protein complex is involved in priming DNA synthesis on single-stranded DNA template in Xenopus egg extract. J. Biol. Chem. 287, 619–627 (2012)
Gu, P. et al. CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. EMBO J. 31, 2309–2321 (2012)
Wang, F. et al. The POT1–TPP1 telomere complex is a telomerase processivity factor. Nature 445, 506–510 (2007)
Latrick, C. M. & Cech, T. R. POT1–TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. EMBO J. 29, 924–933 (2010)
Gao, H., Cervantes, R. B., Mandell, E. K., Otero, J. H. & Lundblad, V. RPA-like proteins mediate yeast telomere function. Nature Struct. Mol. Biol. 14, 208–214 (2007)
Pennock, E., Buckley, K. & Lundblad, V. Cdc13 delivers separate complexes to the telomere for end protection and replication. Cell 104, 387–396 (2001)
Qi, H. & Zakian, V. A. The Saccharomyces telomere-binding protein Cdc13p interacts with both the catalytic subunit of DNA polymerase α and the telomerase-associated Est1 protein. Genes Dev. 14, 1777–1788 (2000)
Grossi, S., Puglisi, A., Dmitriev, P. V., Lopes, M. & Shore, D. Pol12, the B subunit of DNA polymerase α, functions in both telomere capping and length regulation. Genes Dev. 18, 992–1006 (2004)
Martin, V., Du, L. L., Rozenzhak, S. & Russell, P. Protection of telomeres by a conserved Stn1-Ten1 complex. Proc. Natl Acad. Sci. US 104, 14038–14043 (2007)
Damm, K. et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 20, 6958–6968 (2001)
Cristofari, G. & Lingner, J. Telomere length homeostasis requires that telomerase levels are limiting. EMBO J. 25, 565–574 (2006)
Zhao, Y. et al. Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells. Cell 138, 463–475 (2009)
Cristofari, G. et al. Low- to high-throughput analysis of telomerase modulators with Telospot. Nature Methods 4, 851–853 (2007)
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.
The authors declare no competing financial interests.
About this article
Cite this article
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
Nature Reviews Cancer (2022)
Filling in the blanks: how the C-strand catches up to the G-strand at replicating telomeres using CST
Nature Structural & Molecular Biology (2022)