Multiple myeloma-associated hDIS3 mutations cause perturbations in cellular RNA metabolism and suggest hDIS3 PIN domain as a potential drug target.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Mutation*; Exosome Multienzyme Ribonuclease Complex/*genetics ; Multiple Myeloma/*genetics ; RNA/*metabolism; Animals ; Catalytic Domain ; Cell Line ; Cell Proliferation ; Cell Survival ; Exosome Multienzyme Ribonuclease Complex/chemistry ; HEK293 Cells ; Humans ; Phenotype ; RNA Stability ; Saccharomyces cerevisiae Proteins/genetics

hDIS3 is a mainly nuclear, catalytic subunit of the human exosome complex, containing exonucleolytic (RNB) and endonucleolytic (PIN) active domains. Mutations in hDIS3 have been found in ∼10% of patients with multiple myeloma (MM). Here, we show that these mutations interfere with hDIS3 exonucleolytic activity. Yeast harboring corresponding mutations in DIS3 show growth inhibition and changes in nuclear RNA metabolism typical for exosome dysfunction. Construction of a conditional DIS3 knockout in the chicken DT40 cell line revealed that DIS3 is essential for cell survival, indicating that its function cannot be replaced by other exosome-associated nucleases: hDIS3L and hRRP6. Moreover, HEK293-derived cells, in which depletion of endogenous wild-type hDIS3 was complemented with exogenously expressed MM hDIS3 mutants, proliferate at a slower rate and exhibit aberrant RNA metabolism. Importantly, MM mutations are synthetically lethal with the hDIS3 PIN domain catalytic mutation both in yeast and human cells. Since mutations in PIN domain alone have little effect on cell physiology, our results predict the hDIS3 PIN domain as a potential drug target for MM patients with hDIS3 mutations. It is an interesting example of intramolecular synthetic lethality with putative therapeutic potential in humans.

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0 (Saccharomyces cerevisiae Proteins)
63231-63-0 (RNA)
EC 3.1.- (Exosome Multienzyme Ribonuclease Complex)
EC 3.1.13.- (DIS3 protein, S cerevisiae)
EC 3.1.13.- (DIS3 protein, human)

Date Created: 20131024 Date Completed: 20140325 Latest Revision: 20211021

20231215

PMC3902924

10.1093/nar/gkt930

24150935