Structural biology of telomeres and telomerase

  • Eric M. Smith
  • Devon F. Pendlebury
  • Jayakrishnan NandakumarEmail author


Telomeres are protein–DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein–DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein–protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein–protein interfaces within shelterin reveals a series of “domain–peptide” interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.


Telomerase Telomeres Shelterin End replication End protection Meiosis DNA damage response DNA repair ATM ATR 



We thank the entire telomere and telomerase biology community for the groundbreaking research conducted over three decades that has led to our current understanding of chromosome end protection and replication. Although we strived to discuss and cite all publications that are relevant to this topic, we sincerely apologize if we may have overlooked any important contributions. We thank the entire Nandakumar laboratory for critical feedback and proofreading of the manuscript. Author salary/stipend and research in the lab during the writing of this review were funded by R01GM120094 (to J.N.), R01AG050509 (to J.N.; co-investigator), NIH Biology of Aging Training Grant (T32AG000114) awarded to the University of Michigan Geriatrics Center from the National Institute on Aging (fellowship to E.M.S.), and the American Cancer Society Research Scholar grant RSG-17-037-01-DMC (to J.N.).


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Eric M. Smith
    • 1
    • 2
  • Devon F. Pendlebury
    • 1
    • 2
  • Jayakrishnan Nandakumar
    • 1
    • 2
    Email author
  1. 1.Department of Molecular, Cellular, and Developmental BiologyUniversity of MichiganAnn ArborUSA
  2. 2.Program in Chemical BiologyUniversity of MichiganAnn ArborUSA

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