Telomerase adds telomeric repeats at chromosome ends to compensate for the telomere loss that is caused by incomplete genome end replication1. In humans, telomerase is upregulated during embryogenesis and in cancers, and mutations that compromise the function of telomerase result in disease2. A previous structure of human telomerase at a resolution of 8 Å revealed a vertebrate-specific composition and architecture3, comprising a catalytic core that is flexibly tethered to an H and ACA (hereafter, H/ACA) box ribonucleoprotein (RNP) lobe by telomerase RNA. High-resolution structural information is necessary to develop treatments that can effectively modulate telomerase activity as a therapeutic approach against cancers and disease. Here we used cryo-electron microscopy to determine the structure of human telomerase holoenzyme bound to telomeric DNA at sub-4 Å resolution, which reveals crucial DNA- and RNA-binding interfaces in the active site of telomerase as well as the locations of mutations that alter telomerase activity. We identified a histone H2A–H2B dimer within the holoenzyme that was bound to an essential telomerase RNA motif, which suggests a role for histones in the folding and function of telomerase RNA. Furthermore, this structure of a eukaryotic H/ACA RNP reveals the molecular recognition of conserved RNA and protein motifs, as well as interactions that are crucial for understanding the molecular pathology of many mutations that cause disease. Our findings provide the structural details of the assembly and active site of human telomerase, which paves the way for the development of therapeutic agents that target this enzyme.
This is a preview of subscription content
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.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Raw gels are provided in Supplementary Fig. 1. Replicates of the activity assays and immunoblotting experiments shown in Fig. 3d, e and quantification are included in Supplementary Fig. 2. Full mass spectrometry data and coordinates of hTR from DRRAFTER modelling are provided in the Supplementary Information. Cryo-EM maps of the catalytic core, H/ACA lobes and the whole telomerase maps (class 2 and class 5) with both lobes have been deposited with the Electron Microscopy Data Bank under accession numbers EMD-12174, EMD-12177, EMD-12175 and EMD-12176. Refined atomic coordinates for the catalytic core and H/ACA lobes are deposited with the PDB under accession numbers 7BG9 and 7BGB. The rigid body fitted models of the catalytic core and the H/ACA lobes into the whole telomerase maps (class 2 and class 5) are included as a Pymol session in Supplementary Data 2, 3. The BALBES database was provided internally by the BALBES developers, and is available upon request to the corresponding author. Source data are provided with this paper.
Levy, M. Z., Allsopp, R. C., Futcher, A. B., Greider, C. W. & Harley, C. B. Telomere end-replication problem and cell aging. J. Mol. Biol. 225, 951–960 (1992).
Shay, J. W. Role of telomeres and telomerase in aging and cancer. Cancer Discov. 6, 584–593 (2016).
Nguyen, T. H. D. et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature 557, 190–195 (2018).
Blackburn, E. H. & Collins, K. Telomerase: an RNP enzyme synthesizes DNA. Cold Spring Harb. Perspect. Biol. 3, a003558 (2011).
Lingner, J. et al. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276, 561–567 (1997).
Wu, R. A., Upton, H. E., Vogan, J. M. & Collins, K. Telomerase mechanism of telomere synthesis. Annu. Rev. Biochem. 86, 439–460 (2017).
MacNeil, D. E., Bensoussan, H. J. & Autexier, C. Telomerase regulation from beginning to the end. Genes 7, 64 (2016).
Yu, Y.-T. & Meier, U. T. RNA-guided isomerization of uridine to pseudouridine—pseudouridylation. RNA Biol. 11, 1483–1494 (2014).
Sarek, G., Marzec, P., Margalef, P. & Boulton, S. J. Molecular basis of telomere dysfunction in human genetic diseases. Nat. Struct. Mol. Biol. 22, 867–874 (2015).
Li, L. & Ye, K. Crystal structure of an H/ACA box ribonucleoprotein particle. Nature 443, 302–307 (2006).
Li, S. et al. Reconstitution and structural analysis of the yeast box H/ACA RNA-guided pseudouridine synthase. Genes Dev. 25, 2409–2421 (2011).
Bai, X. C., Rajendra, E., Yang, G., Shi, Y. & Scheres, S. H. W. Sampling the conformational space of the catalytic subunit of human γ-secretase. eLife 4, e11182 (2015).
Nakane, T., Kimanius, D., Lindahl, E. & Scheres, S. H. W. Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION. eLife 7, e36861 (2018).
Kappel, K. et al. De novo computational RNA modeling into cryo-EM maps of large ribonucleoprotein complexes. Nat. Methods 15, 947–954 (2018).
Podlevsky, J. D. & Chen, J. J. Evolutionary perspectives of telomerase RNA structure and function. RNA Biol. 13, 720–732 (2016).
Jiang, J. et al. Structure of telomerase with telomeric DNA. Cell 173, 1179–1190 (2018).
Wu, R. A., Tam, J. & Collins, K. DNA-binding determinants and cellular thresholds for human telomerase repeat addition processivity. EMBO J. 36, 1908–1927 (2017).
Qi, X. et al. RNA/DNA hybrid binding affinity determines telomerase template-translocation efficiency. EMBO J. 31, 150–161 (2012).
Bryan, T. M., Goodrich, K. J. & Cech, T. R. A mutant of Tetrahymena telomerase reverse transcriptase with increased processivity. J. Biol. Chem. 275, 24199–24207 (2000).
Schaich, M. A. et al. Mechanisms of nucleotide selection by telomerase. eLife 9, e55438 (2020).
Miller, M. C., Liu, J. K. & Collins, K. Template definition by Tetrahymena telomerase reverse transcriptase. EMBO J. 19, 4412–4422 (2000).
Nair, D. T., Johnson, R. E., Prakash, S., Prakash, L. & Aggarwal, A. K. Replication by human DNA polymerase-ι occurs by Hoogsteen base-pairing. Nature 430, 377–380 (2004).
Chen, J. L., Opperman, K. K. & Greider, C. W. A critical stem-loop structure in the CR4–CR5 domain of mammalian telomerase RNA. Nucleic Acids Res. 30, 592–597 (2002).
Robart, A. R. & Collins, K. Investigation of human telomerase holoenzyme assembly, activity, and processivity using disease-linked subunit variants. J. Biol. Chem. 285, 4375–4386 (2010).
Kim, N. K., Theimer, C. A., Mitchell, J. R., Collins, K. & Feigon, J. Effect of pseudouridylation on the structure and activity of the catalytically essential P6.1 hairpin in human telomerase RNA. Nucleic Acids Res. 38, 6746–6756 (2010).
Long, F., Vagin, A. A., Young, P. & Murshudov, G. N. BALBES: a molecular-replacement pipeline. Acta Crystallogr. D 64, 125–132 (2008).
Davey, C. A., Sargent, D. F., Luger, K., Maeder, A. W. & Richmond, T. J. Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 a resolution. J. Mol. Biol. 319, 1097–1113 (2002).
Schnapp, G., Rodi, H.-P., Rettig, W. J., Schnapp, A. & Damm, K. One-step affinity purification protocol for human telomerase. Nucleic Acids Res. 26, 3311–3313 (1998).
Palka, C., Forino, N. M., Hentschel, J., Das, R. & Stone, M. D. Folding heterogeneity in the essential human telomerase RNA three-way junction. RNA 26, 1787–1800 (2020).
Fu, D. & Collins, K. Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs. Mol. Cell 11, 1361–1372 (2003).
Egan, E. D. & Collins, K. An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. Mol. Cell. Biol. 32, 2428–2439 (2012).
Tycowski, K. T., Shu, M. D., Kukoyi, A. & Steitz, J. A. A conserved WD40 protein binds the Cajal body localization signal of scaRNP particles. Mol. Cell 34, 47–57 (2009).
Venteicher, A. S. et al. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323, 644–648 (2009).
Theimer, C. A. et al. Structural and functional characterization of human telomerase RNA processing and cajal body localization signals. Mol. Cell 27, 869–881 (2007).
Jády, B. E., Bertrand, E. & Kiss, T. Human telomerase RNA and box H/ACA scaRNAs share a common Cajal body-specific localization signal. J. Cell Biol. 164, 647–652 (2004).
Parks, J. W. & Stone, M. D. Coordinated DNA dynamics during the human telomerase catalytic cycle. Nat. Commun. 5, 4146 (2014).
Patrick, E. M., Slivka, J. D., Payne, B., Comstock, M. J. & Schmidt, J. C. Observation of processive telomerase catalysis using high-resolution optical tweezers. Nat. Chem. Biol. 16, 801–809 (2020).
Nandakumar, J. et al. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492, 285–289 (2012).
Latrick, C. M. & Cech, T. R. POT1–TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. EMBO J. 29, 924–933 (2010).
Zhong, F. L. et al. TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell 150, 481–494 (2012).
Sexton, A. N., Youmans, D. T. & Collins, K. Specificity requirements for human telomere protein interaction with telomerase holoenzyme. J. Biol. Chem. 287, 34455–34464 (2012).
Upton, H. E., Hong, K. & Collins, K. Direct single-stranded DNA binding by Teb1 mediates the recruitment of Tetrahymena thermophila telomerase to telomeres. Mol. Cell. Biol. 34, 4200–4212 (2014).
Jiang, J. et al. Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions. Science 350, aab4070 (2015).
Witkin, K. L. & Collins, K. Holoenzyme proteins required for the physiological assembly and activity of telomerase. Genes Dev. 18, 1107–1118 (2004).
Stone, M. D. et al. Stepwise protein-mediated RNA folding directs assembly of telomerase ribonucleoprotein. Nature 446, 458–461 (2007).
Greider, C. W. Regulating telomere length from the inside out: the replication fork model. Genes Dev. 30, 1483–1491 (2016).
Margalef, P. et al. Stabilization of reversed replication forks by telomerase drives telomere catastrophe. Cell 172, 439–453 (2018).
Sauer, P. V. et al. Mechanistic insights into histone deposition and nucleosome assembly by the chromatin assembly factor-1. Nucleic Acids Res. 46, 9907–9917 (2018).
Wu, R. A., Dagdas, Y. S., Yilmaz, S. T., Yildiz, A. & Collins, K. Single-molecule imaging of telomerase reverse transcriptase in human telomerase holoenzyme and minimal RNP complexes. eLife 4, e08363 (2015).
Luger, K., Rechsteiner, T. J. & Richmond, T. J. in Methods in Enzymology Vol. 304 (eds. Wassarman P. M. & Wolffe, A. P.) 3–19 (Elsevier, 1999).
Nguyen, T. H. D. Structural and Biochemical Studies of Spliceosomal Activation. PhD thesis, Univ. of Cambridge (2014).
Goodrich, J. A. & Kugel, J. F. Binding and Kinetics for Molecular Biologists (Cold Spring Harbor Laboratory, 2007).
Mastronarde, D. N. Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 152, 36–51 (2005).
Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7, e42166 (2018).
Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).
Zivanov, J., Nakane, T. & Scheres, S. H. W. Estimation of high-order aberrations and anisotropic magnification from cryo-EM data sets in RELION-3.1. IUCrJ 7, 253–267 (2020).
Rosenthal, P. B. & Henderson, R. Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy. J. Mol. Biol. 333, 721–745 (2003).
Chen, S. et al. High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy. Ultramicroscopy 135, 24–35 (2013).
Brown, A. et al. Tools for macromolecular model building and refinement into electron cryo-microscopy reconstructions. Acta Crystallogr. D 71, 136–153 (2015).
Vagin, A. & Teplyakov, A. Molecular replacement with MOLREP. Acta Crystallogr. D 66, 22–25 (2010).
Casañal, A., Lohkamp, B. & Emsley, P. Current developments in Coot for macromolecular model building of electron cryo-microscopy and crystallographic data. Protein Sci. 29, 1055–1064 (2020).
Chou, F.-C., Echols, N., Terwilliger, T. C. & Das, R. RNA structure refinement using the ERRASER–Phenix pipeline. Methods Mol. Biol. 1320, 269–282 (2016).
Afonine, P. V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D 68, 352–367 (2012).
Murshudov, G. N. et al. REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr. D 67, 355–367 (2011).
Nicholls, R. A., Fischer, M., McNicholas, S. & Murshudov, G. N. Conformation-independent structural comparison of macromolecules with ProSMART. Acta Crystallogr. D 70, 2487–2499 (2014).
Williams, C. J. et al. MolProbity: more and better reference data for improved all-atom structure validation. Protein Sci. 27, 293–315 (2018).
Tang, G. et al. EMAN2: an extensible image processing suite for electron microscopy. J. Struct. Biol. 157, 38–46 (2007).
Goddard, T. D. et al. UCSF ChimeraX: meeting modern challenges in visualization and analysis. Protein Sci. 27, 14–25 (2018).
Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
Podlevsky, J. D., Bley, C. J., Omana, R. V., Qi, X. & Chen, J. J. The telomerase database. Nucleic Acids Res. 36, D339–D343 (2008).
Tesmer, V. M., Smith, E. M., Danciu, O., Padmanaban, S. & Nandakumar, J. Combining conservation and species-specific differences to determine how human telomerase binds telomeres. Proc. Natl Acad. Sci. USA 116, 26505–26515 (2019).
We thank the MRC-LMB EM facility staff for access and support of electron microscopy sample preparation and data collection; J. Grimmett and T. Darling for maintaining the computing facility; the LMB mass spectrometry facility for running mass spectrometry experiments; S. Scotcher and the LMB workshop team for making our electrophoresis gel systems; K. Muir and D. Barford for sharing human histone expression constructs; K. Kappel for advice on DRRAFTER modelling; the K. Nagai, J. Löwe and L. Passmore laboratories for sharing reagents and equipment; members of the laboratories of K.C. and E. Nogales for past technical support; and D. Barford, A. Carter, E. Nogales, L. Passmore and S. Scheres for critical reading of the manuscript. R.R. is supported by a National Science Foundation Graduate Fellowship. This work was funded by a UKRI-Medical Research Council grant to T.H.D.N. (MC_UP_1201/19), an NIH grant to K.C. (GM054198) and NIH grants to R.D. (GM122579 and GM121487).
The authors declare no competing interests.
Peer review information Nature thanks Thomas Cech and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Summary of the data processing strategies that yielded the reconstructions described in this Article.
a, Gold-standard FSC curves for maps of H/ACA lobe, the catalytic core and the best two full-length classes. Resolutions were estimated at FSC = 0.143. b, FSC curves for the refined H/ACA and catalytic core models versus the corresponding maps. Resolutions were estimated at FSC = 0.5. c–f, Local resolution estimated by RELION 3.154 for the H/ACA lobe (c), the catalytic core (d), full-length 3D class 2 (e) and full-length 3D class 5 (f). For direct comparisons, the same local resolution range (3.3–16 Å) was used for all maps.
a, e, f, i, k, l, Full densities of TERT (a), histone H2A (e), histone H2B (f), TCAB1 (i), 5′ H/ACA tetramer (k) and 3′ H/ACA tetramer (l). b, Close-up view of the active site density of TERT with an empty nucleotide-binding pocket (Extended Data Fig. 6f). c, d, Representative electron microscopy densities of TERT. g, h, j, Representative electron microscopy densities of histone H2A (g), histone H2B (h) and TCAB1 (j). m, Close-up view of the density of the N-terminal extension of the 5′ dyskerin bound to a hydrophobic pocket within the 3′ dyskerin (Fig. 4c). n, Close-up view of the density of helix 352–375 of the 3′ dyskerin bound to the equivalent hydrophobic pocket as in m within the 5′ dyskerin (Fig. 4d). o, Close-up view of the density of the P8 stem loop of hTR, which contains the CAB and BIO boxes that interact with TCAB1 and the 3′ NHP2 (Extended Data Figs. 4l, 8d). p, Close-up view of the density of the H and ACA boxes interacting with the two dyskerin molecules (Extended Data Figs. 4k, 8c).
a, Secondary structure schematic of hTR based on the structure. This figure was modified from the telomerase database70. b, c, Full density of hTR in the catalytic core (b) and the H/ACA lobe (c). d, Close-up view of the density of interactions between the DNA substrate and hTR template (Fig. 2b). e, Close-up view of density of the DNA substrate and neighbouring residues of TERT (Extended Data Fig. 6d). f, Close-up view of density of the RNA template region and neighbouring residues of TERT (Extended Data Fig. 6e). g, Density of the P6.1 hairpin of the CR4/5 domain. Labelled residues are highlighted in Fig. 3a. h, Close-up review of the density of the P6.1 stem loop interacting with residues of the CTE domain of TERT (g, Fig. 3a). i, Close-up view of the density of residue L1019 of TERT, which interacts with the two flipped-out nucleotides, U177 of the PK and U307 of the P6.1 stem loop as highlighted in Fig. 3b. j, Representative density of the PK containing the base triples, which are highlighted in black. Nucleotide U113 is modelled but not visible in this view. k, Density of the H and ACA boxes (Extended Data Fig. 3p). l, Density of the P8 stem loop (Extended Data Fig. 3o).
Extended Data Fig. 5 Multibody refinement and conformational dynamics analysis of the full-length structure.
a, Summary of the multibody refinement strategy and principal component analysis13. The best two subsets from global 3D classification were subjected to multibody refinement using two masks for the H/ACA lobe (yellow) and the catalytic core (cyan). b, Principal component analysis for 3D class 2. c, Principal component analysis for 3D class 5. The first and last frames of the eigenvector series of the first six principal components are shown. Curved arrows indicate the movements. d, Top 10 hTR ensembles modelled by DRRAFTER into the refined full-length 3D class 2 map (Supplementary Data 2). e, Top 10 hTR ensembles modelled by DRRAFTER into the refined full-length 3D class 5 map (Supplementary Data 3). hTR is shown in blue, and the protein subunits are in grey.
a, Domain architecture of human TERT and conserved motifs that are often observed in reverse transcriptases70. b, TERT conserved motifs shown in a, and their interactions with the template and DNA substrate. c, A model for the telomerase catalytic cycle. The template region of hTR is divided into an alignment region and a template region. The telomeric DNA repeat first binds to the alignment region, followed by six consecutive nucleotide additions using the template region. After the synthesis of the full telomeric repeat, the DNA substrate translocates to bind the alignment region to start another round of repeat synthesis. The state captured in our structure is indicated with an asterisk. d, Interactions between the 3′ telomeric TTAGGG repeat of the substrate and TERT. e, Interactions between the template region of hTR and TERT. f, TERT active site in a prenucleotide state. D712, D868 and D869 form the catalytic triad for nucleotide addition (Extended Data Fig. 3b). g, Modelled dTTP (PDB 1T3N22) in the vacant nucleotide site of TERT. The C2 ribose is indicated. h, Structure of human TERT with PK/t and CR4/5 domains of hTR and DNA. i, Electrostatic surface potential of human TERT with hTR and the DNA substrate shown in the same view as in h. The highlighted human TEN–IFD–TRAP interface (in blue) is positively charged and could potentially bind the 5′ end of the DNA substrate in human telomerase. j, IFD–TRAP and TEN domains of TERT. Residues that are known to affect TPP1 binding to TERT are highlighted as spheres71. The proposed DNA path would bring it close to the proposed TPP1-binding site on the TEN domain. k, Model of TPP1–POT1 bound to human TEN domain, based on the Tetrahymena p50–TEB complex. Despite the similar overall domain arrangements, the domains of Tetrahymena and human TERT do not align well as a whole. To obtain the model, we superposed the Tetrahymena TEN domain–p50–TEB1–TEB2–TEB3 complex (PDB 6D6V16) onto the human TEN domain. l, Model of telomerase catalytic cycle. Telomerase template RNA binds the telomeric DNA substrate by base-pairing. The DNA-binding sites on TERT are indicated by yellow stars. One binding site is provided by motif T and the CTE domain of TERT near the active site, as observed in the structure (Fig. 2d and d). The second binding site is proposed to be provided by the TEN domain at the 5′ end of the DNA. After the synthesis of a full telomeric repeat, the nascent DNA undergoes translocation and rebinding to the template RNA. We propose that the two DNA-binding sites form an anchor site to allow DNA retention for multiple rounds of repeat synthesis.
Extended Data Fig. 7 Identification of histone H2A and H2B as subunits of the human telomerase holoenzyme.
a, Three-dimensional classification of the catalytic core (dataset 1), showing the presence of the unaccounted-for density (in yellow). The best class (boxed) has the most homogenous density, and was selected for the final refinement. Similar observations were made with the second dataset. b, The 8 Å catalytic core map (in grey) with the previously unmodelled density (in yellow)3 (left) and with the model of the catalytic core obtained from this work fitted into it (right). The density assigned as the histone H2A–H2B dimer coincided with the unmodelled density from the previous work. c, The refined catalytic core map, with hTR, TERT and histone H2A–H2B segmented in different colours. d, Top, interactions between CR4/5 and the histone H2A–H2B dimer in human telomerase. Bottom, electrostatic surface potential of the histone dimer and the positively charged surface used for interacting with the CR4/5. e, Nucleosome structure. The histone H2A–H2B dimer is coloured and oriented the same way as in d. This shows that the histone H2A–H2B dimer uses the same surface to bind both nucleosomal DNA and CR4/5 (PDB 1KX527). f, Purified histone H2A–H2B and CR4/5 RNA used for electrophoretic mobility shift assay in Fig. 3f. No RNA ladders were loaded with the CR4/5 RNA. g, Immunoblots of crude lysate of HEK 293T cells transfected with twin Strep-TERT and hTR expression constructs (input) and oligonucleotide elution from 2′-O-methyl purification (Fig. 3c). These samples were immunoblotted for Strep and histones H2A, H2B, H3 and H4. The presence of histones H2A, H2B, H3 and H4 was also confirmed by mass spectrometry (Supplementary Data 4). h, Immunoblots of crude lysate of HEK 293T cells (input) and oligonucleotide elution from 2′-O-methyl purification. These samples were immunoblotted for dyskerin, and histones H2A, H2B, H3 and H4. i, Structure of the Tetrahymena TRBD–CTE–p65 and stem loop 4 (SL4) (PDB 6D6V16). j, Structure of human TRBD–CTE–H2A–H2B and CR4/5. k, Quantification of the electrophoretic mobility shift assays shown in Fig. 3f for Kd determination. ‘Total fraction bound’ reflects the quantification of free probe depletion against total probe with increasing histone concentration. ‘Specific fraction bound’ reflects the quantification of the increasing discrete shifted complex band against total probe with increasing histone concentration. Points represent values from three independent replicates (Supplementary Fig. 1). l, Superposition of the histone octamer structure, with flexible histone tails removed, onto the histone H2A–H2B dimer bound to the human telomerase catalytic core in two different views (PDB 1KX527).
a, Front (left) and back (right) views of the H/ACA RNP with subunits coloured as indicated. b, Secondary structure schematic of the H/ACA domain of hTR. c, Left, close-up view of the H and ACA boxes, and their interactions with each other and with the two dyskerin molecules (Extended Data Figs. 3p, 4k). Right, sequences of H and ACA boxes, with conserved nucleotides highlighted in bold. d, Left, close-up view of P8 stem loop and interactions between the CAB and BIO boxes with TCAB1 and NHP2 (Extended Data Figs. 3o, 4l). Right, a schematic of these interactions.
This file contains Supplementary Text, Supplementary Figures 1 – 2 and Supplementary Table 1.
Pymol session showing the top 10 hTR models obtained from DRRAFTER for the catalytic core.
About this article
Cite this article
Ghanim, G.E., Fountain, A.J., van Roon, AM.M. et al. Structure of human telomerase holoenzyme with bound telomeric DNA. Nature 593, 449–453 (2021). https://doi.org/10.1038/s41586-021-03415-4
Nature Structural & Molecular Biology (2021)
Cell Research (2021)
Nature Catalysis (2021)