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

• 成果类型: Article
• 署名作者: Balch, Sebastian; Sekne, Zala; Franco-Echevarria, Elsa; Ludzia, Patryk; Kretsch, Rachael C.; Sun, Wenqing; Yu, Haopeng; Ghanim, George E.; Thorkelsson, Sigurdur; Ding, Yiliang; Das, Rhiju; Nguyen, Thi Hoang Duong
• 署名单位: MRC Laboratory Molecular Biology; Stanford University; Northeast Normal University - China; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); John Innes Center; Stanford University; Howard Hughes Medical Institute; Stanford University; University of Cambridge; Princeton University; Thermo Fisher Scientific
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11936
• DOI: 10.1126/science.adr5817
• 发表日期: 2025-07-10
• 关键词: type-1 reverse-transcriptase; active human telomerase; g-quadruplex; refinement; Visualization; purification; RECRUITMENT; biogenesis; mutations; mechanism

摘要

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.