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

Area of Science:

• Molecular Biology
• Epigenetics
• RNA Biology

Background:

• Telomerase RNA (TERC) modifications are largely unexplored.
• N6-Methyladenosine (m6A) is a key RNA modification.
• Telomerase dysfunction is linked to aging and disease.

Purpose of the Study:

• To map m6A modifications on TERC.
• To elucidate the regulatory role of TERC m6A in telomerase function.
• To identify proteins interacting with m6A-modified TERC.

Main Methods:

• m6A mapping on TERC.
• Assessing telomerase activity and telomere length.
• Co-immunoprecipitation to study protein interactions.
• Knockdown and rescue experiments in alveolar epithelial cells.

Main Results:

• TERC is methylated at A111 and A435 by METTL3.
• TERC m6A deficiency reduces telomerase activity and telomere length by disrupting TERC-TERT association.
• YTHDC1 binds TERT and recognizes m6A sites on TERC, acting as a scaffold.
• YTHDC1 knockdown phenocopies METTL3 deficiency.
• Wild-type YTHDC1, but not truncated YTHDC1, rescues cellular phenotypes.

Conclusions:

• m6A modification of TERC is a central regulator of telomerase function.
• YTHDC1 plays a critical scaffolding role in TERT-TERC assembly.
• This study provides new insights into telomerase regulation and telomere-related diseases.