Structure of human telomerase holoenzyme with bound telomeric DNA

Nature. 2021 May;593(7859):449-453. doi: 10.1038/s41586-021-03415-4. Epub 2021 Apr 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Cryoelectron Microscopy*
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • DNA / ultrastructure*
  • Histones / chemistry
  • Histones / metabolism
  • Holoenzymes / chemistry
  • Holoenzymes / metabolism
  • Holoenzymes / ultrastructure
  • Humans
  • Models, Molecular
  • Mutation
  • Nucleic Acid Conformation
  • Nucleotide Motifs
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • RNA / chemistry
  • RNA / metabolism
  • RNA / ultrastructure
  • Ribonucleoproteins / chemistry
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism
  • Ribonucleoproteins / ultrastructure
  • Telomerase / chemistry*
  • Telomerase / metabolism
  • Telomerase / ultrastructure*
  • Telomere* / genetics
  • Telomere* / metabolism
  • Telomere* / ultrastructure


  • Histones
  • Holoenzymes
  • Protein Subunits
  • Ribonucleoproteins
  • telomerase RNA
  • RNA
  • DNA
  • Telomerase