Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism.
Ilaria GrittiVeronica BassoDarawan RinchaiFederica CoriglianoSilvia PivettiMarco GaviraghiDalia RosanoDavide MazzaSara BarozziMarco RoncadorGiovanni ParmigianiGaëlle LegubeDario ParazzoliDavide CittaroDavide BedognettiAnna MondinoSimona SegallaGiovanni TononPublished in: The EMBO journal (2022)
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.
Keyphrases
- circulating tumor
- nucleic acid
- multiple myeloma
- single molecule
- cell free
- dna repair
- dna damage
- dna damage response
- newly diagnosed
- induced apoptosis
- genome wide
- cell proliferation
- oxidative stress
- end stage renal disease
- copy number
- transcription factor
- case report
- cell cycle arrest
- dna methylation
- signaling pathway
- patient reported outcomes
- squamous cell