Exosome-mediated decay of unstable long extended precursors of human telomerase RNA is dependent on 5′-cap trimethylation

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.