The structure of human CST reveals a decameric assembly bound to telomeric DNA
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Abstract
Architecture of DNA-organizing complex: The highly conserved mammalian CTC1-STN1-TEN1 (CST) complex is critical for genome stability and telomere maintenance. Lim et al. solved the structure of the human CST complex using cryo–electron microscopy. CST forms an unprecedented and substantial decameric supercomplex triggered by telomeric single-stranded binding. This decameric form with single-stranded DNA–binding capacity of up to 10 telomeric repeats, suggested the possibility of CST organizing telomere overhangs into compact and restrictive structures in a manner similar to the nucleosome's organization of double-stranded DNA. This work provides a platform for understanding the mechanisms of various CST functions. Science , this issue p. 1081
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CTC1-STN1-TEN1 controls DNA break repair pathway choice via DNA end resection blockade
Rogers, C. M., Kaur, H., Swift, M. L., Raina, V. B., Zhou, S., Kawale, A. S., Syed, S., Kelly, K., Jasper, A. M., Salunkhe, S., et al. (2025) · Science · doi:10.1126/science.adt3034 · Cited by 19
CST–Polymeraseα-primase solves a second telomere end-replication problem
Takai, H., Aria, V., Borges, P., Yeeles, J. T. P., & de Lange, T. (2024) · Nature · doi:10.1038/s41586-024-07137-1 · Cited by 19 · see citing works
RPA engages telomeric G-quadruplexes more effectively than CST
Olson, C. L., Barbour, A., Wieser, T. A., & Wuttke, D. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad315 · Cited by 19 · see citing works
“To determine Tm, ε for a wavelength of a characteristic peak for each oligonucleotide (see Supplementary Figure S2 for wavelength chosen for each oligonucleotide) was plotted against temperature and data were fit to a Boltzmann sigmoidal curve (Eq.”
BackgroundMethodResultInfluentialSelf-citationAckerson, S. M., Gable, C. I., & Stewart, J. (2020) · Cell Cycle · doi:10.1080/15384101.2020.1849979 · Cited by 19 · see citing works
“Structural studies demonstrate a high degree of structural homology between the OB-folds in CST and RPA [24,25].”
BackgroundStructural Motifs at the Telomeres and Their Role in Regulatory Pathways
Alanazi, A. F. R., Parkinson, G. N., & Haider, S. (2024) · Biochemistry · doi:10.1021/acs.biochem.4c00023 · Cited by 18
Barbour, A., & Wuttke, D. (2023) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2023.102611 · Cited by 14 · see citing works
Self-citationWieser, T. A., & Wuttke, D. (2022) · Biochemistry · doi:10.1021/acs.biochem.2c00504 · Cited by 14 · see citing works
Self-citationPol α-primase dependent nuclear localization of the mammalian CST complex
Kelich, J. M., Papaioannou, H., & Skordalakes, E. (2021) · Communications Biology · doi:10.1038/s42003-021-01845-4 · Cited by 13 · see citing works
A mechanistic model of primer synthesis from catalytic structures of DNA polymerase α–primase
Mullins, E. A., Salay, L., Durie, C., Bradley, N. P., Jackman, J. E., Ohi, M., Chazin, W., & Eichman, B. (2023) · bioRxiv · doi:10.1101/2023.03.16.533013 · Cited by 11
“Based on the evolutionarily relationship between CST and RPA 66 , we believe RPA likely scaffolds pol α –primase in a similar manner, explaining RPA-dependent stimulation of primer synthesis by pol α –primase 67 .”
CST/Polα/primase-mediated fill-in synthesis at DSBs
Mirman, Z., Cai, S. W., & de Lange, T. (2022) · Cell Cycle · doi:10.1080/15384101.2022.2123886 · Cited by 11 · see citing works
“CST is related to the abundant ssDNA-binding factor RPA [24,25].”
BackgroundMethodInfluentialOlson, C. L., Barbour, A., & Wuttke, D. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00818-3 · Cited by 11
Self-citationOB-Folds and Genome Maintenance: Targeting Protein–DNA Interactions for Cancer Therapy
Par, S., Vaides, S., VanderVere-Carozza, P., Pawelczak, K., Stewart, J., & Turchi, J. (2021) · Cancers · doi:10.3390/cancers13133346 · Cited by 11
“In humans, purified CST can form a multimeric structure, composed of ten separate CST complexes [36].”
BackgroundInfluentialDynamic DNA Shortening by Telomere-Binding Protein Cdc13.
Lin, Y.-Y., Li, M.-H., Chang, Y.-C., Fu, P., Ohniwa, R. L., Li, H.-W., & Lin, J.-J. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c00820 · Cited by 11 · see citing works
STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer
Dong, D., Zhou, Z., Zhu, M., Hou, Z.-Y., Chen, M., Gong, J., Zhao, X.-Y., Yan, A., Liang, H., & Yin, Y.-X. (2025) · Nature Communications · doi:10.1038/s41467-025-63083-0 · Cited by 10 · see citing works
Human CST Stimulates Base Excision Repair to Prevent the Accumulation of Oxidative DNA Damage
Wysong, B. C., Schuck, P. L., Sridharan, M., Carrison, S., Murakami, Y., Balakrishnan, L., & Stewart, J. A. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168672 · Cited by 10 · see citing works
“19,38,57 However, this may provide some insight into how CST promotes BER.”
A mechanistic model of primer synthesis from catalytic structures of DNA polymerase α–primase
Mullins, E. A., Salay, L., Durie, C., Bradley, N. P., Jackman, J. E., Ohi, M., Chazin, W. J., & Eichman, B. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01227-4 · Cited by 10 · see citing works
“At replication forks, polα–primase interacts with several proteins associated with the replisome, including MCM10, AND-1, RPA, RFC, polδ and the CMG helicase 19,36,60 , as well as multiple nucleosome core proteins 61,62 .”
Models for Human Telomere C-Strand Fill-In by CST-Polα-Primase
He, Q., & Lim, C. J. (2023) · TIBS -Trends in Biochemical Sciences. Regular ed · doi:10.1016/j.tibs.2023.07.008 · Cited by 10
Self-citationCTC1 OB-B interaction with TPP1 terminates telomerase and prevents telomere overextension
Wang, H., Ma, T., Zhang, X., Chen, W., Lan, Y., Kuang, G., Hsu, S., He, Z., Chen, Y.-X., Stewart, J., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad237 · Cited by 10 · see citing works
“We found the C-terminal OB deletion mutants ( F-G and G) lost interaction with STN1 (Figure 1B), which was consistent with previous findings of a strong interaction between CTC1 OB-G and the OB-fold domain on STN1 (35).”
BackgroundResultInfluentialTelomeric chromatin structure.
Soman, A., Korolev, N., & Nordenskiöld, L. (2022) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2022.102492 · Cited by 10 · see citing works
Roy, S., Pramanik, P., & Bhattacharya, S. (2025) · Biochimie · doi:10.1016/j.biochi.2025.04.004 · Cited by 9 · see citing works
Jaiswal, R., Lei, K.-H., Chastain, M., Wang, Y., Shiva, O., Li, S., You, Z.-S., Chi, P., & Chai, W.-H. (2023) · Nature Communications · doi:10.1038/s41467-023-43685-2 · Cited by 9 · see citing works
Shepelev, N., Dontsova, O., & Rubtsova, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24055027 · Cited by 9 · see citing works
“Recent cryo-EM results showed that CST forms a ring-like decameric DNA–protein supercomplex [300].”
BackgroundRiquelme, J., Takada, S., van Dijk, T., Pena, F., Boogaard, M., van Duyvenvoorde, H. V., Pico-Knijnenburg, I., Wit, J., van der Burg, M., Mericq, V., et al. (2021) · Hormone Research in Paediatrics · doi:10.1159/000520410 · Cited by 9
Zahid, S., Aloe, S., Sutherland, J., Holloman, W., & Lue, N. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010182 · Cited by 8 · see citing works
When the Ends Justify the Means: Regulation of Telomere Addition at Double-Strand Breaks in Yeast
Hoerr, R. E., Ngo, K., & Friedman, K. L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.655377 · Cited by 7 · see citing works
“While the identity of the human ortholog of Cdc13 remains unclear (Ge et al., 2020; Lim et al., 2020), results described here in yeast raise the interesting possibility that recurrent sites of de novo telomere addition observed in some disease states may require the human Ctc1/Stn1/Ten1 complex (Stewart et al.”
BackgroundChevalier, R., Pienkowski, V. M., Jullien, N., Caron, L., Verdier‐Pinard, P., Magdinier, F., & Robin, J. D. (2025) · Aging Cell · doi:10.1111/acel.70027 · Cited by 7 · see citing works
“…RNA) (Azzalin et al. 2007; Feretzaki et al. 2019) and a trimeric nucleoprotein complex (CST, composed of CTC1, STN1, and TEN1) binding to single-stranded telomeric DNA (telomeric overhang) where it is involved in chromosome end capping and telomere length regulation (Lim et al. 2020).”
Communication between DNA polymerases and Replication Protein A within the archaeal replisome
Martínez-Carranza, M., Vialle, L., Madru, C., Cordier, F., Tekpinar, A., Haouz, A., Legrand, P., Meur, R. A. L., England, P., Dulermo, R., et al. (2024) · bioRxiv · doi:10.1038/s41467-024-55365-w · Cited by 7 · see citing works
The CST complex facilitates cell survival under oxidative genotoxic stress
Hara, T., Nakaoka, H., Miyoshi, T., & Ishikawa, F. (2023) · PLoS ONE · doi:10.1371/journal.pone.0289304 · Cited by 7
Olson, C. L., & Wuttke, D. (2024) · Biomolecules · doi:10.3390/biom14030263 · Cited by 6 · see citing works
“Similar to RPA, CST is a heterotrimeric protein complex, in humans consisting of CTC1, STN1, and TEN1 with the majority of the domains consisting of OB-folds [142] (Figure 3A).”
BackgroundInfluentialSelf-citationNasheuer, H., & Onwubiko, N. O. (2023) · Genes · doi:10.3390/genes14051012 · Cited by 6 · see citing works
“The smallest subunit TEN1/TEN1L comprises an OB-fold dom in [64].”
BackgroundCST–Polymeraseα-primase solves a second telomere end-replication problem
Takai, H., Aria, V., Borges, P., Yeeles, J. T. P., & de Lange, T. (2023) · bioRxiv · doi:10.1101/2023.10.26.564248 · Cited by 5
Haghizadeh, A., Iftikhar, M., Dandpat, S. S., & Simpson, T. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032668 · Cited by 5 · see citing works
Loss of Ten1 in mice induces telomere shortening and models human dyskeratosis congenita
Sanz-Moreno, A., Becker, L., Xie, K., da Silva-Buttkus, P., Dragano, N., Aguilar-Pimentel, A., Amarie, O., Calzada-Wack, J., Kraiger, M., Leuchtenberger, S., et al. (2025) · Science Advances · doi:10.1126/sciadv.adp8093 · Cited by 4 · see citing works
“There is evidence that the CST complex forms oligomeric supercomplexes ( 18 ), suggesting that its precise conformation is important for CST function.”
Control of telomere length in yeast by SUMOylated PCNA and the Elg1 PCNA unloader
Singh, P., Gazy, I., & Kupiec, M. (2023) · bioRxiv · doi:10.7554/elife.86990 · Cited by 4 · see citing works
Coloma, J., González-Rodríguez, N., Balaguer, F. A., Gmurczyk, K., Aicart-Ramos, C., Nuero, O. M., Luque-Ortega, J. R., Calugaru, K., Lue, N., Moreno-Herrero, F., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkac1261 · Cited by 3 · see citing works
“Human CTC1 is a 1217 amino acid protein harboring seven oligonucleotide/oligosaccharide-binding fold (OB-fold) domains (21), whereas S.”
BackgroundResultInfluentialMolecular mechanisms of telomere biology disorders
Grill, S., & Nandakumar, J. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.014017 · Cited by 2 · see citing works
“The recently solved cryo-EM structure of human CST bound to ss DNA reveals the distribution of disease mutations across the multiple OB domains of the CTC1 protein (161).”
BackgroundChai, W.-H., Chastain, M., Shiva, O., & Wang, Y. (2021) · Biology · doi:10.3390/biology10100977 · Cited by 2
Calugaru, K., Yu, E. Y., Huang, S., González-Rodríguez, N., Coloma, J., & Lue, N. F. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf245 · Cited by 1 · see citing works
“Indeed, the interaction with PP represents the only physical contacts for the Ten1 L34 loop observed in all available structures of the CST complex [ 33 , 58–61 ].”
Dimerization of Cdc13 is essential for dynamic DNA exchange on telomeric DNA
Nickens, D., Gray, S. J., Simmons, R. H., & Bochman, M. L. (2025) · bioRxiv · doi:10.1101/2025.03.25.645294 · Cited by 1
“…DDE, or does the interaction with Stn1 and Ten1 inhib activity? ibit The analogous human complex (CTC1-STN1-TEN1) displays 1:1:1 stoichiometry in so with 10 CST complexes assembling into a ring-shaped super-complex when bound to (TTAGGG ssDNA, as demonstrated by cryo-electron microscopy (45).”
Unwrap RAP1’s Mystery at Kinetoplastid Telomeres
Li, B.-B. (2024) · Biomolecules · doi:10.3390/biom14010067 · Cited by 1 · see citing works
“They bind the telomere 3 ′ overhang as a heterotrimer [36], which is structurally similar to the RPA complex [34,37–39].”
BackgroundSifri, C., Hoeg, L., Durocher, D., & Setiaputra, D. (2023) · bioRxiv · doi:10.1101/2023.01.12.523815 · Cited by 1 · see citing works
“, 2020) and the CST complex consisting of CTC1-STN1-TEN1 (PDB ID:6W6W; Lim et al., 2020), further supporting the utility of this approach.”
BackgroundMethodInfluentialMacNeill, S. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.675229 · Cited by 1
Telomere maintenance and genome stability
Huang, W., Hernandez-Sanchez, W., Xu, M.-Y., & Taylor, D. (2021) · Genome Stability · doi:10.1016/b978-0-12-803309-8.00021-5 · Cited by 1 · see citing works
Mechanisms and disease relevance of DNA break repair pathway choice.
Swift, M. L., Rogers, C. M., Kaur, H., Chowdhury, D., & Sung, P. M. (2026) · Nature reviews. Molecular cell biology · doi:10.1038/s41580-026-01026-3
Laghari, Z. A., Li, N., Gayybov, S., Wang, Q.-E., & Chai, W.-H. (2026) · NAR Cancer · doi:10.1093/narcan/zcag023
“Instead, the overall complex assembly and stability reply on STN1, which acts as a bridging subunit between CTC1 and TEN1 [ 79 ].”
Inhibition of lagging strand replication by G-rich telomeric DNA and the shelterin subunit POT1
Leonard-Booker, C., Mazzucco, G., Fisher, C. E., Hussain, K., Deegan, T., Doksani, Y., & Douglas, M. E. (2026) · EMBO Journal · doi:10.1038/s44318-026-00844-7
“CST was puri fi ed as described (Lim et al, 2020) with some minor alterations.”
Laghari, Z. A., Li, N., Gayybov, S., Wang, Q.-E., & Chai, W.-H. (2026) · bioRxiv · doi:10.64898/2026.05.15.725290
“Therefore, while our data identify STN1 as the only CST component whose upregulation is associated with and sufficient to promote PARPi resistance-associated phenotypes, additional studies will be required to determine whether these effects reflect a unique function of STN1 or enhanced activity of…”
Holbrooks, J. S., Loveless, C. A., Vogler, K. A., Reed, S., Duvall, G. H., Romney, C. V., Ackerson, S. M., Kircher, M. B., & Stewart, J. A. (2026) · Journal of Cell Science · doi:10.1242/jcs.264269
“CST consists of numerous oligonucleotide-oligosaccharide binding folds (OB-folds), which allow it to bind to ssDNA (Lim et al., 2020).”
Zhou, P., Liu, Y., He, X.-L., Wang, Z., Li, J.-D., Zhang, Y., Kong, Q., Zhang, X., Guo, H., Cao, D., et al. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.152464
Single-stranded DNA-binding proteins at healthy and diseased telomeres.
Lescalet, G., Monterroso, A., Kochman, R., Coulon, S., & Maréchal, A. (2026) · TIBS -Trends in Biochemical Sciences. Regular ed · doi:10.1016/j.tibs.2025.11.010
Knowles, S., Wang, F., Bosland, M., Gaddameedhi, S., & Chai, W.-H. (2025) · PLoS ONE · doi:10.1371/journal.pone.0326647
Zou, M.-B., Tian, F.-J., Zheng, W.-W., Jiang, M.-Z., Zhang, S., Liu, X.-L., Ma, C., Zhao, M.-P., Dai, L., Li, C.-N., et al. (2025) · bioRxiv · doi:10.1101/2025.11.03.685478
Stn1 supports Mec1 function in protecting stalled replication forks from degradation
Casari, E., Corallo, F., Milani, L. E., Tisi, R., & Longhese, M. P. (2025) · PLoS Genetics · doi:10.1371/journal.pgen.1011917
Dimerization of Cdc13 is essential for dynamic DNA exchange on telomeric DNA
Nickens, D., Gray, S. J., Simmons, R. H., & Bochman, M. L. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110496
“The analogous human complex (CTC1-STN1-TEN1) displays 1:1:1 stoichiometry in solution and itself oligomerizes (36), but CTC1 shares little homology with Cdc13.”
Lescale, C., Marton, T., Vaysse, A., Rode, G., Vincendeau, E., Libri, A., Dossin, F., & Deriano, L. (2025) · European Journal of Immunology · doi:10.1002/eji.202451585
“In addition, CST is known to limit G-quadruplex (G4) accumulation at telomeres and other genome sites [9, 32] possibly by assembling as a decamer structure that could act as a nucleosome equivalent for G-rich ssDNA [29].”
Wentworth, K., & Nandakumar, J. (2024) · Molecules and Cells · doi:10.1016/j.molcel.2024.06.030
Amaral, E. D. O. S., Jara-Espejo, M., & Line, S. R. P. (2024) · Journal of mammalian evolution · doi:10.1007/s10914-024-09719-2
“…be recruited to such areas to perform functions related to telomere maintenance, chromatin remodeling, and regulation of transcription and translation (Thakur et al. 2009; Petr et al. 2016; Zhu et al. 2019; Lim et al. 2020; Simko et al. 2020; Mei et al. 2021; Varshney et al. 2021; Shu et al. 2022).”
Tethering CST to the telomerase catalytic core-the p50 linchpin.
Joseph, N. A., & Chen, L.-Y. (2022) · Structure · doi:10.1016/j.str.2022.11.005
Chevalier, R., Pienkwoski, V. M., Jullien, N., Caron, L., Magdinier, F., & Robin, J. D. (2022) · bioRxiv · doi:10.1101/2022.09.30.510336
Structure of telomerase-bound CST with Polymerase α-PrimasePreprint
He, Y., Song, H., Chan, H., Wang, Y.-Q., Liu, B.-C., Sušac, L., Zhou, H. Z., & Feigon, J. (2021) · bioRxiv · doi:10.1101/2021.12.28.474374
CST interacts with the cohesin complex and promotes chromosome cohesionPreprint
Schuck, P. L., & Stewart, J. (2021) · bioRxiv · doi:10.1101/2021.04.11.439363
“Like RPA, CST contains multiple oligosaccharide-oligonucleotide folds (OB-folds) that allow dynamic binding to the DNA (11,12).”
Background
- Authors
- Lim, C. J., Barbour, A. T., Zaug, A. J., Goodrich, K. J., McKay, A. E., Wuttke, D. S., & Cech, T. R.
- Affiliations
- University of Colorado Boulder (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wuttke, Deborah S.
- Cech, Thomas R.
- ORCID
- Venue
- Science
- Published
- 2020-06-05
- Volume
- 368
- Issue
- 6495
- Pages
- 1081-1085
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7559292
- OpenAlex
- W3033318436
- Cited by
- 111
- References
- 62
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 16 · 2023: 27 · 2022: 17 · 2021: 26 · 2020: 5
- FWCI
- 11.28
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (MCB 1716425)
- National Institutes of Health (R01GM099705, R01GM059414, K99GM131023, T32GM008759)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- CST complex, telomere maintenance, single-stranded DNA, telomeric DNA, Stn1, allosteric regulation, replication protein A, cryo-EM structure
- MeSH terms
- Protein Domains, DNA, Single-Stranded, Humans, Protein Binding, Telomere, Cryoelectron Microscopy, Telomere-Binding Proteins, Multiprotein Complexes, Replication Protein A, Protein Multimerization, HEK293 Cells, Telomere Homeostasis
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