Inhibition of 5`- Cap Trimethylation Prevents Exosome Targeting of Telomerase RNA, Despite Promoting Increased 3`- end Oligoadenylation

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 trimethylation results in accumulation of nucleolar 3`- end extended precursors, evading MTR4 recognition and degradation by the exosome, which in turn facilitates processing into mature hTR. 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 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.