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Multiple myeloma-associated hDIS3 mutations cause perturbations in cellular RNA metabolism and suggest hDIS3 PIN domain as a potential drug target.
Tomecki, Rafal; Drazkowska, Karolina; Kucinski, Iwo; Stodus, Krystian; Szczesny, Roman J; Gruchota, Jakub; Owczarek, Ewelina P; Kalisiak, Katarzyna; Dziembowski, Andrzej.
Afiliação
  • Tomecki R; Department of Biophysics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland, Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland and International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland.
Nucleic Acids Res ; 42(2): 1270-90, 2014 Jan.
Article em En | MEDLINE | ID: mdl-24150935
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: RNA / Complexo Multienzimático de Ribonucleases do Exossomo / Mieloma Múltiplo / Mutação Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: RNA / Complexo Multienzimático de Ribonucleases do Exossomo / Mieloma Múltiplo / Mutação Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article