Figure 6: A feed-forward pathway regulating hTR maturation is determined by the H/ACA domain.

A. A feed-forward pathway governs maturation of human telomerase RNA (Wild-type cells): hTR extended precursors mature directly or are fed into a side pathway and oligoadenylated by PAPD5. Oligoadenylated precursors may be deadenylated by PARN to form mature hTR, or destroyed by the RNA exosome. Final trimming of hTR precursor is achieved through a 3’-5’ RNA exonuclease.

(PARN-KO cells): In the absence of PARN, oligoadenylated intermediates cannot robustly convert to mature hTR. There is a relative increase in oligoadenylated hTR precursors, and a loss of mature hTR.

(PAPD5-KO cells): In the absence of PAPD5, fewer hTR precursors are fed into the cycle of adenylation and deadenylation, leading to rapid maturation of hTR molecules.

B. The hTR H/ACA domain and dyskerin constitute a 3’ end formation module. The H/ACA domain in the presence of dyskerin promotes transcriptional termination and oligoadenylation of an extended precursor.