Abstract
Mutations that impact maturation of human telomerase RNA (hTR) are common in telomere biology disorders. Here, we describe sequential posttranscriptional modifications that coordinate hTR biogenesis and decay. Initially, TGS1-mediated 5'-cap trimethylation targets long genomically extended hTR precursors for degradation. Prevention of 5'-cap trimethylation results in accumulation of nucleolar 3'-end extended precursors, evading MTR4 recognition and degradation by the exosome. In a second step, 3'-end oligoadenylation by PAPD5 promotes degradation of mature hTR, a process that remains dependent on 5'-cap modifications, as prevention of trimethylation inhibits decay of heavily 3'-end oligoadenylated molecules. Combined inhibition of 5'-cap trimethylation and 3'-end oligoadenylation synergistically increases hTR in cells harboring pathogenic mutations in telomerase. These data reveal a precise interplay between 5'- and 3'-end posttranscriptional modifications that dictate hTR fate and highlight the potential of RNA therapeutics for treatment of telomere biology disorders.