Abstract
The nuclear RNA exosome, a conserved 3'→5' ribonuclease complex, degrades the vast majority of RNA polymerase II output, including promoter upstream transcripts, enhancer RNAs, antisense transcripts, and retrotransposon-derived RNAs. Beyond this housekeeping role, the exosome acts as an epigenetic effector, and its dysfunction underlies a growing spectrum of human disease. Here we integrate recent structural, genomic, and disease-focused studies into a unified model of the exosome as a guardian of the epigenome. We describe how MTR4-containing adaptor complexes TRAMP, NEXT, and PAXT confer substrate selectivity, and how the exosome enforces heterochromatic silencing in concert with HP1 proteins and the Human Silencing Hub (HUSH) complex and preserves three-dimensional genome architecture at insulators and enhancers, such as the protocadherin locus where RNA surveillance, CTCF insulation, and heterochromatin converge. We then examine the consequences of failure: exosomopathies such as pontocerebellar hypoplasia, loss of DIS3- and PAXT-mediated tumor suppression in cancer, and age-related erosion of surveillance that permits transposable element de-repression, RIG-1/MDA5 and cGAS-STING-driven inflammation, cellular senescence, and neurodegeneration. We conclude that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target.