ArticleNucleic acids research2014
Multiple myeloma-associated hDIS3 mutations cause perturbations in cellular RNA metabolism and suggest hDIS3 PIN domain as a potential drug target.
Article in Nucleic acids research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 76 citations in OpenAlex.
- Whole-exome sequencing of primary plasma cell leukemia discloses heterogeneous mutational patterns.Oncotarget · 2015Trial
- Prognostic impact of monosomy 13 and deletion of 13q in multiple myeloma patients undergoing upfront autologous transplantation.British journal of haematology · 2026Article
- DIS3 mutations enhance AID-driven translocations during B-cell activation, promoting transformation to multiple myeloma.Nature communications · 2026Article
- DIS3 licenses B cells for plasma cell differentiation in humans.Cellular & molecular immunology · 2026Article
- The 3'-5' exoribonuclease ISG20L2 contributes to 3' terminus maturation of 18S and 28S ribosomal RNAs.Nucleic acids research · 2025Article
- Structure-specific nucleases in genome dynamics and strategies for targeting cancers.Journal of molecular cell biology · 2024Review
- Article
- DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis.The Journal of clinical endocrinology and metabolism · 2023Observational
- In vivo characterization of the critical interaction between the RNA exosome and the essential RNA helicase Mtr4 in Saccharomyces cerevisiae.G3 (Bethesda, Md.) · 2023Article
- How hydrolytic exoribonucleases impact human disease: Two sides of the same story.FEBS open bio · 2023Review
- Review
- Dissecting Trypanosoma brucei RRP44 function in the maturation of segmented ribosomal RNA using a regulated genetic complementation system.Nucleic acids research · 2023Article
- Trypanosoma brucei RRP44: a versatile enzyme for processing structured and non-structured RNA substrates.Nucleic acids research · 2023Article
- MPP6 stimulates both RRP6 and DIS3 to degrade a specified subset of MTR4-sensitive substrates in the human nucleus.Nucleic acids research · 2022Article
- DIS3 mutations in multiple myeloma impact the transcriptional signature and clinical outcome.Haematologica · 2022Article
- Rapid factor depletion highlights intricacies of nucleoplasmic RNA degradation.Nucleic acids research · 2022Article
- Reverse Genetic Screen for Deleterious Recessive Variants in the Local Simmental Cattle Population of Switzerland.Animals : an open access journal from MDPI · 2021Article
- Landscape of functional interactions of human processive ribonucleases revealed by high-throughput siRNA screenings.iScience · 2021Article
- RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis.Nucleic acids research · 2021Article
- Post-transcriptional control of cellular differentiation by the RNA exosome complex.Nucleic acids research · 2020Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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