Abstract
ABSTRACTThe exosome functions to regulate the cellular transcriptome through RNA biogenesis, surveillance, and decay. Mutations in Dis3, a catalytic subunit of the RNA exosome with separable endonuclease and exonuclease activities, are linked to multiple myeloma. Here we report that a cancer-associated DIS3 allele, dis3E729K, provides evidence for DIS3 functioning in mitotic fidelity in yeast. This dis3E729K allele does not induce defects in 7S→5.8S rRNA processing, although it elicits a requirement for P-body function. While it does not significantly influence cell cycle progression alone, the allele reduces the efficiency of cell cycle arrest in strains with defects in kinetochore assembly. Finally, point mutations in the exonuclease domains of yeast Dis3 elicit genome instability phenotypes; however, these DIS3 mutations do not increase DNA damage or RNA processing defects that lead to the accumulation of polyadenylated RNA in the nucleus. These data suggest that specific DIS3 activities support mitotic fidelity in yeast.
Highlights
Dis3 is one of two catalytic components, along with Rrp6, of the eukaryotic RNA exosome complex
We sequenced the dis3-ts allele to investigate this phenotype with respect to Dis3 activity but found that dis3-ts carries 10 non-synonymous variants throughout the length of the gene (Figure 1(a))
We wished to determine if this cancer-associated DIS3 point mutation induced cellular defects similar to those previously reported for dis3ts
Summary
Dis3 is one of two catalytic components, along with Rrp6, of the eukaryotic RNA exosome complex. The dis3E729K mutant has been studied alongside control strains that are temperature sensitive or have endonuclease or exonuclease deficiency; these strains have allowed us to link Dis3 exonuclease domain function to chromosome stability, with exonuclease mutants exhibiting reduced fitness and increased CIN.
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