TY - JOUR
T1 - Cryo-EM structure of human telomerase dimer reveals H/ACA RNP-mediated dimerization
AU - Balch, Sebastian
AU - Sekne, Zala
AU - Franco-Echevarría, Elsa
AU - Ludzia, Patryk
AU - Kretsch, Rachael C.
AU - Sun, Wenqing
AU - Yu, Haopeng
AU - Ghanim, George E.
AU - Thorkelsson, Sigurdur
AU - Ding, Yiliang
AU - Das, Rhiju
AU - Nguyen, Thi Hoang Duong
N1 - Publisher Copyright:
© 2025 American Association for the Advancement of Science. All rights reserved.
PY - 2025/7/10
Y1 - 2025/7/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105010612285
UR - https://www.scopus.com/pages/publications/105010612285#tab=citedBy
U2 - 10.1126/science.adr5817
DO - 10.1126/science.adr5817
M3 - Article
C2 - 40638752
AN - SCOPUS:105010612285
SN - 0036-8075
VL - 389
JO - Science
JF - Science
IS - 6756
M1 - eadr5817
ER -