RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat Production.

RNA polymerase II transcribes the vast majority of the mammalian genome, yet most of this output, including promoter upstream transcripts (PROMPTs), enhancer RNAs (eRNAs), antisense transcripts, and retrotransposon-derived RNAs, must be rapidly degraded []. The machinery principally responsible for this turnover is the nuclear RNA exosome, a conserved multi-subunit ribonuclease complex first identified in []. Beyond its housekeeping role, the exosome also functions as an epigenetic effector: it enforces transcriptional silencing at heterochromatin by degrading noncoding RNAs that would otherwise accumulate [,], shapes Polycomb Repressive Complex 2 (PRC2) activity by clearing poly(A)+ transcripts that titrate PRC2 away from chromatin [], influences three-dimensional genome architecture by processing RNAs at insulator elements and enhancers [,], and collaborates with the Human Silencing Hub (HUSH) complex and HP1 proteins to degrade retrotransposon transcripts that trigger innate immune activation [,,,]. Critically, the noncoding transcripts subject to this surveillance are not merely transcriptional noise, and the exosome does not act on them indiscriminately. Because the exosome degrades the bulk of Pol II noncoding output, a transcript’s stability is determined largely by whether it can evade decay. Conserved, functional long noncoding RNAs (lncRNAs) are enriched among the escapers: they are either retained in chromatin-bound ribonucleoprotein complexes or exhibit stabilizing features such as splicing or protective 3′-end structures in place of a poly(A) tail, such as the triple helices in lncRNAs MALAT1 and NEAT1 that block 3′→5′ exonucleolytic attack []. Although such lncRNAs typically show poor primary-sequence conservation, their functions are conserved across evolutionarily distant species through selection on secondary structure, genomic synteny, and conserved protein partners [,,]. In addition to RNA degradation the exosome is also important for processing noncoding RNA: through distributive 3′-end trimming it matures a conserved repertoire of structured ncRNAs, including ribosomal, small nucleolar, and small nuclear RNAs [,]. The exosome thus functions as a curator that sets the threshold separating functional noncoding RNAs from pervasive transcriptional noise—a regulated surveillance program rather than a disposal system.