3′End Maturation of Human Telomerase Rna Component (Terc) and Its Effects on Telomere Dynamics

Abstract

Telomerase RNA Component (TERC) is the non-coding RNA template and scaffold of the telomerase holoenzyme. TERC level has been shown to be a limiting factor for telomerase activity, lower levels resulting in telomere diseases such as dyskeratosis congenita (DC), idiopathic pulmonary fibrosis; and higher levels being observed in various cancers. In contrast to telomerase RNAs in other species, the mechanisms of human TERC biogenesis and accumulation has not been well understood. Recently, it has been shown that mutations in the gene encoding poly(A) specific ribonuclease (PARN) causes telomere disease. Here, using somatic cells and induced pluripotent stem cells (iPSC) from DC patients with PARN mutations, we show that PARN is required for the 3′ end maturation of the TERC. Patient cells as well as immortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERC RNA 3′ termini reveals that PARN is required for removal of post-transcriptionally acquired oligo(A) tails that target nuclear RNAs for degradation. Previously, PARN has been shown to deadenylate certain non-coding RNAs such as small nucleolar RNAs and microRNAs that are adenylated by the non-canonical poly(A) polymerase. Here we find that PAPD5 is responsible for the post-transcriptional oligoadenylation of TERC and this oligo(A) tail destabilizes nascent TERC transcripts. Disrupting PAPD5 favors TERC 3′ end maturation by the PARN and increases steady state TERC levels. In PARN-mutant iPSCs from DC patients, in which TERC biogenesis is impaired, PAPD5 knockdown restores TERC RNA levels, telomerase activity and telomere elongation. Our results show that TERC biogenesis and steady state levels depends on the balance of PARN and PAPD5. Here, we demonstrate a role for PARN and PAPD5 in regulating telomere length homeostasis and identify it as a potential target for the therapeutic manipulation of telomerase.