AATF/Che-1 localizes to paraspeckles and suppresses R-loops accumulation and interferon activation in Multiple Myeloma.

Autor: Bruno T; SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Corleone G; SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Catena V; SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Cortile C; SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy., De Nicola F; SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Fabretti F; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany., Gumenyuk S; Hematology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Pisani F; Hematology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Mengarelli A; Hematology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Passananti C; Department of Molecular Medicine, CNR-Institute of Molecular Biology and Pathology, Sapienza University of Rome, Rome, Italy., Fanciulli M; SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2022 Nov 17; Vol. 41 (22), pp. e109711. Date of Electronic Publication: 2022 Aug 05.
DOI: 10.15252/embj.2021109711
Abstrakt: Several kinds of stress promote the formation of three-stranded RNA:DNA hybrids called R-loops. Insufficient clearance of these structures promotes genomic instability and DNA damage, which ultimately contribute to the establishment of cancer phenotypes. Paraspeckle assemblies participate in R-loop resolution and preserve genome stability, however, the main determinants of this mechanism are still unknown. This study finds that in Multiple Myeloma (MM), AATF/Che-1 (Che-1), an RNA-binding protein fundamental to transcription regulation, interacts with paraspeckles via the lncRNA NEAT1_2 (NEAT1) and directly localizes on R-loops. We systematically show that depletion of Che-1 produces a marked accumulation of RNA:DNA hybrids. We provide evidence that such failure to resolve R-loops causes sustained activation of a systemic inflammatory response characterized by an interferon (IFN) gene expression signature. Furthermore, elevated levels of R-loops and of mRNA for paraspeckle genes in patient cells are linearly correlated with Multiple Myeloma progression. Moreover, increased interferon gene expression signature in patients is associated with markedly poor prognosis. Taken together, our study indicates that Che-1/NEAT1 cooperation prevents excessive inflammatory signaling in Multiple Myeloma by facilitating the clearance of R-loops. Further studies on different cancer types are needed to test if this mechanism is ubiquitously conserved and fundamental for cell homeostasis.
(© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
Databáze: MEDLINE
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