AGO2 promotes telomerase activity and interaction between the telomerase components TERT and TERC

Abstract Telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) constitute the core telomerase enzyme that maintains the length of telomeres. Telomere maintenance is affected in a broad range of cancer and degenerative disorders. Taking advantage of gain‐ and loss‐of‐function approaches, we show that Argonaute 2 (AGO2) promotes telomerase activity and stimulates the association between TERT and TERC. AGO2 depletion results in shorter telomeres as well as in lower proliferation rates in vitro and in vivo . We also demonstrate that AGO2 interacts with TERC and with a newly identified sRNA ( terc ‐sRNA), arising from the H/ACA box of TERC. Notably, terc ‐sRNA is sufficient to enhance telomerase activity when overexpressed. Analyses of sRNA‐Seq datasets show that terc ‐sRNA is detected in primary human tissues and increases in tumors as compared to control tissues. Collectively, these data uncover a new layer of complexity in the regulation of telomerase activity by AGO2 and might lay the foundation for new therapeutic targets in tumors and telomere diseases.