YTHDC1 Orchestrates Telomerase Assembly via Scaffold-Mediated TERT-TERC Interaction.

Abstract

Telomerase RNA (TERC) is subject to various modifications, yet the implications of these modifications for telomerase biology remain largely unexplored. In this study, we conducted a comprehensive mapping of N6-Methyladenosine (m6A) modifications within TERC RNA and elucidated their regulatory role in telomerase function. Our findings demonstrate that TERC undergoes methylation at adenosine residues A111 and A435 by METTL3. A deficiency in TERC m6A, which is also linked to various human telomerase disease-related mutations and deletions, significantly reduces telomerase activity and telomere length by disrupting the association between TERC and TERT. Mechanistically, YTHDC1 was identified as a scaffold facilitating the interaction between TERT and TERC, binding to TERT while recognizing m6A sites on TERC. Knockdown of YTHDC1 significantly diminished the interaction between TERT and TERC, thereby reducing telomerase activity and phenocopying the deficiency of METTL3. Furthermore, reconstituting wild-type YTHDC1 rescued telomere attrition, proliferation defects, and senescence in YTHDC1-knockdown alveolar epithelial cells, whereas truncated YTHDC1 (which retains m6A recognition but lacks TERT-binding capacity) failed to restore these phenotypes. Collectively, our work establishes m6A modification of TERC as a central regulator of telomerase function and reveals YTHDC1's scaffolding role in TERT-TERC assembly, shedding new light on the regulation of telomerase and related diseases.