Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism.
DNA damage repair
DNA:RNA Hybrids
R-loops
interferon
multiple myeloma
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
17 11 2022
17 11 2022
Historique:
revised:
25
07
2022
received:
16
02
2021
accepted:
23
09
2022
pubmed:
11
10
2022
medline:
22
11
2022
entrez:
10
10
2022
Statut:
ppublish
Résumé
The ribonuclease DIS3 is one of the most frequently mutated genes in the hematological cancer multiple myeloma, yet the basis of its tumor suppressor function in this disease remains unclear. Herein, exploiting the TCGA dataset, we found that DIS3 plays a prominent role in the DNA damage response. DIS3 inactivation causes genomic instability by increasing mutational load, and a pervasive accumulation of DNA:RNA hybrids that induces genomic DNA double-strand breaks (DSBs). DNA:RNA hybrid accumulation also prevents binding of the homologous recombination (HR) machinery to double-strand breaks, hampering DSB repair. DIS3-inactivated cells become sensitive to PARP inhibitors, suggestive of a defect in homologous recombination repair. Accordingly, multiple myeloma patient cells mutated for DIS3 harbor an increased mutational burden and a pervasive overexpression of pro-inflammatory interferon, correlating with the accumulation of DNA:RNA hybrids. We propose DIS3 loss in myeloma to be a driving force for tumorigenesis via DNA:RNA hybrid-dependent enhanced genome instability and increased mutational rate. At the same time, DIS3 loss represents a liability that might be therapeutically exploited in patients whose cancer cells harbor DIS3 mutations.
Identifiants
pubmed: 36215697
doi: 10.15252/embj.2021108040
pmc: PMC9670201
doi:
Substances chimiques
Ribonucleases
EC 3.1.-
DNA
9007-49-2
RNA
63231-63-0
DIS3 protein, human
EC 3.1.13.-
Exosome Multienzyme Ribonuclease Complex
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e108040Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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