The exosome complex possesses 3'-5' exonuclease and endoribonucleolytic activities that are essential for diverse ribonucleolytic processes in both the nucleus and the cytoplasm (2, 12, 13). The nuclear exosome is associated with the TRAMP complex and is involved in RNA catabolic processes including RNA surveillance (14, 15 and references therein), pre-mRNA turnover (16) and the production of mature 3' ends for snoRNAs, snRNAs and rRNAs (12, 17 and references therein). The cytoplasmic exosome is associated with Ski7p and the SKI complex and is involved in RNA catabolic processes that include both the routine turnover of normal mRNA (18) as well as the degradation of aberrant mRNAs (19 and references therein). The 10-subunit core exosome complex (Csl4p, Rrp4p, Rrp40p, Ski6p, Rrp42p, Rrp43p, Rrp45p, Rrp46p, Mtr3p, Dis3p) is the same in both locations, but the nuclear exosome contains an additional subunit (Rrp6p) and two additional accessory factors (Lrp1p, Mpp6p) (13).

Although the exosome was originally described as a "complex of exonucleases," with multiple subunits proposed to have RNase activity (2), later work has shown that this mechanism is unlikely in yeast. With the exception of Ski6p, none of the yeast subunits that show homology to E. coli RNase PH retain the active site residues seen in the bacterial or archael enzymes. Further research has also demonstrated that most, if not all, detectable enzymatic activity resides in the Dis3p and Rrp6p subunits (5, 6).

DIS3 encodes the catalytic subunit of the core exosome complex, and possesses both 3'-5' exonuclease activity and endoribonuclease activity (6, 5, 8, 9, 10). In addition to its nuclease activity, Dis3p is required for recognition of certain exosome substrates (20). Dis3p associates with the exosome through its N-terminus, which mediates interactions with other exosome subunits such as Rrp45p, Rrp43p, and Ski6p (9, 21). Dis3p appears to function in the Ran signaling pathway, as evidenced by its direct binding to the Ran GTPase Gsp1p and its ability to stimulate the guanine nucleotide exchange activity of RCC1, the human homolog of the Ran nucleotide exchange factor Srm1p (1). Mutants null for dis3 are inviable, point mutations in either Dis3p nuclease domain results in slow growth, and conditional and repressible mutants of dis3 accumulate processing intermediates and aberrant forms of various classes of RNAs, including mRNAs and rRNAs (1, 8, 10, 22, 2).

Although Dis3p shares a similar linear arrangement of domains with the bacterial exonuclease RNase II, the tertiary structures of the two enzymes differ and Dis3p is biochemically more like bacterial RNase R (7 and references therein). DIS3 is conserved among eukaryotes, and both fission yeast dis3 and human DIS3 proteins are able to rescue S. cerevisiae dis3 mutant phenotypes (1, 4).

Last updated: 2009-09-09