Bruno, Tiziana, Corleone, Giacomo, Catena, Valeria ORCID: 0000-0002-9639-1944, Cortile, Clelia, De Nicola, Francesca, Fabretti, Francesca, Gumenyuk, Svitlana, Pisani, Francesco, Mengarelli, Andrea ORCID: 0000-0002-2606-2467, Passananti, Claudio and Fanciulli, Maurizio (2022). AATF/Che-1 localizes to paraspeckles and suppresses R-loops accumulation and interferon activation in Multiple Myeloma. Embo J., 41 (22). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bruno, TizianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corleone, GiacomoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Catena, ValeriaUNSPECIFIEDorcid.org/0000-0002-9639-1944UNSPECIFIED
Cortile, CleliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Nicola, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fabretti, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gumenyuk, SvitlanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pisani, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mengarelli, AndreaUNSPECIFIEDorcid.org/0000-0002-2606-2467UNSPECIFIED
Passananti, ClaudioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fanciulli, MaurizioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-675238
DOI: 10.15252/embj.2021109711
Journal or Publication Title: Embo J.
Volume: 41
Number: 22
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LONG NONCODING RNA; DNA-DAMAGE; CELL; TRANSCRIPTION; EXPRESSION; SUBUNIT; BINDING; NEAT1; PROLIFERATION; INHIBITIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/67523

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