DIS3

DIS3, also known as RRP44, is a conserved ribonuclease that forms the catalytic core of the eukaryotic exosome complex. The DIS3 gene encodes a multifunctional RNase whose activity is essential for RNA processing and degradation, influencing a wide range of RNA species and quality control pathways.

DIS3 has a modular architecture that includes an N-terminal PIN domain, which can confer endoribonuclease activity in some contexts, followed by an RNB family exoribonuclease domain. It also contains cold-shock domains and an S1 RNA-binding domain that help it interact with RNA substrates. In the exosome, DIS3 associates with the core subunits of the exosome to execute 3' to 5' exonuclease activity and coordinate RNA processing with degradation.

Functionally, DIS3 participates in the maturation and turnover of various RNAs, including ribosomal RNA, small nucleolar RNA, messenger RNA, and aberrant transcripts. It contributes to RNA quality control and surveillance, ensuring the removal of damaged or unwanted RNAs. In the nucleus, DIS3 is involved in processing and surveillance of nuclear RNAs, while its cytoplasmic counterpart DIS3L supports exosome-mediated decay in the cytoplasm. The exosome often works in concert with RNA helicases such as MTR4 to remodel RNA substrates.

Evolutionarily, DIS3 is conserved from yeast to humans. In higher eukaryotes, it is primarily nuclear, with the paralog DIS3L providing cytoplasmic activity; both are essential components of the exosome machinery.

Clinical significance is highlighted by the identification of DIS3 mutations in certain cancers, notably multiple myeloma, where alterations can affect RNA metabolism and genome stability and may have prognostic or therapeutic relevance.