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

MRC Laboratory of Molecular Biology, Cambridge, UK.MRC Laboratory of Molecular Biology, Cambridge, UK. · pubmed

Paper

Abstract

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.

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Research summary

The paper claims that the dimerization of human telomerase, mediated by the H/ACA RNP, is crucial for its assembly and function in telomere maintenance. This research is relevant as it addresses the fundamental mechanisms of telomerase, which is directly linked to cellular aging and the maintenance of chromosome integrity, thus contributing to our understanding of aging processes.

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