Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism

• DOI: 10.15252/embj.2021108040
• Publication Date: 2022-10-10T20:26:52Z
• Authors: Ilaria Gritti; Veronica Basso; Darawan Rinchai; Federica Corigliano; Silvia Pivetti; Marco Gaviraghi; Dalia Rosano; Davide Mazza; Sara Barozzi; Marco Roncador; Giovanni Parmigiani; Gaelle Legube; Dario Parazzoli; Davide Cittaro; Davide Bedognetti; Anna Mondino; Simona Segalla; Giovanni Tonon
• Keywords: 0301 basic medicine; DNA Repair; Exosome Multienzyme Ribonuclease Complex; Recombinational DNA Repair; R-loops; interferon; Articles; DNA; Genomic Instability; 3. Good health; multiple myeloma; 03 medical and health sciences; Ribonucleases; DNA damage repair; Humans; RNA; DNA:RNA Hybrids; Multiple Myeloma; Homologous Recombination

The ribonuclease DIS3 is one of the most frequently mutated genes in hematological cancer multiple myeloma, yet basis its tumor suppressor function this disease remains unclear. Herein, exploiting TCGA dataset, we found that plays a prominent role DNA damage response. inactivation causes genomic instability by increasing mutational load, and pervasive accumulation DNA:RNA hybrids induces double-strand breaks (DSBs). hybrid also prevents binding homologous recombination (HR) machinery to breaks, hampering DSB repair. DIS3-inactivated cells become sensitive PARP inhibitors, suggestive defect Accordingly, myeloma patient for harbor an increased burden overexpression pro-inflammatory interferon, correlating with hybrids. We propose loss be driving force tumorigenesis via hybrid-dependent enhanced genome rate. At same time, represents liability might therapeutically exploited patients whose mutations.