Cryo-EM structure of human telomerase dimer reveals H/ACA RNP-mediated dimerization
- Sebastian Balch
- Zala Sekne
- Elsa Franco-Echevarría
- Patryk Ludzia
- Rachael C. Kretsch
- Wenqing Sun
- Haopeng Yu
- George E. Ghanim
- Sigurdur Thorkelsson
- Yiliang Ding
- Rhiju Das
- Thi Hoang Duong Nguyen
2025-07-10
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.