Cryo-EM structure of human telomerase dimer reveals H/ACA RNP-mediated dimerization

• Published in: Science (American Association for the Advancement of Science) Vol. 389; no. 6756; p. eadr5817
• Main Authors: Balch, Sebastian, Sekne, Zala, Franco-Echevarría, Elsa, Ludzia, Patryk, Kretsch, Rachael C., Sun, Wenqing, Yu, Haopeng, Ghanim, George E., Thorkelsson, Sigurdur, Ding, Yiliang, Das, Rhiju, Nguyen, Thi Hoang Duong
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 10.07.2025
• Subjects: Abundance; Aging; Chromosomes; Composition; Cores; Cryoelectron Microscopy; Deoxyribonucleic acid; Dimerization; Dimers; Disruption; DNA; DNA - chemistry; DNA biosynthesis; Electron microscopy; Eukaryotes; Evolution; Fractionation; Histone H2A; Histones; Humans; Language Maintenance; Localization; Maintenance; Microscopy; Molecular interactions; Molecular structure; Monomers; Mutagenesis; Mutation; Phenotypes; Protein Multimerization; Proteins; Ribonucleic acid; RNA; RNA - chemistry; RNA-directed DNA polymerase; Telomerase; Telomerase - chemistry; Telomerase - genetics; Telomerase - ultrastructure; Telomerase reverse transcriptase; Telomere - chemistry; Telomeres; Transmission electron microscopy
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adr5817

Telomerase ribonucleoprotein (RNP) synthesizes telomeric repeats at chromosome ends using a telomerase reverse transcriptase (TERT) and a telomerase RNA (hTR in humans). Previous structural work showed that human telomerase is typically monomeric, containing a single copy of TERT and hTR. Evidence for dimeric complexes exists, although the composition, high-resolution structure, and function remain elusive. Here, we report the cryo–electron microscopy (cryo-EM) structure of a human telomerase dimer bound to telomeric DNA. The structure reveals a 26-subunit assembly and a dimerization interface mediated by the Hinge and ACA box (H/ACA) RNP of telomerase. Premature aging disease mutations map to this interface. Disrupting dimer formation affects RNP assembly, bulk telomerase activity, and telomere maintenance in cells. Our findings address a long-standing enigma surrounding the telomerase dimer and suggest a role for the dimer in telomerase assembly. Telomerase maintains chromosome ends (telomeres) and is an essential factor in genome stability, aging, and cancer. Although telomerase is known to function as a monomer, evidence has hinted at a possible dimeric form. Using cryo–electron microscopy, Balch et al . resolved the structure of a catalytically active telomerase dimer, revealing that it forms through interactions mediated by the H/ACA ribonucleoprotein. Mutations at this interface are linked to premature aging disorders. Disrupting dimerization impairs telomerase assembly and telomere maintenance, suggesting that the dimer acts as an assembly intermediate. These findings reshape our understanding of telomerase biogenesis and its regulation in cells. —Di Jiang