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AATF/Che‐1 localizes to paraspeckles and suppresses R‐loops accumulation and interferon activation in Multiple Myeloma
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9670196/ https://www.ncbi.nlm.nih.gov/pubmed/35929179 http://dx.doi.org/10.15252/embj.2021109711 |
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author | Bruno, Tiziana Corleone, Giacomo Catena, Valeria Cortile, Clelia De Nicola, Francesca Fabretti, Francesca Gumenyuk, Svitlana Pisani, Francesco Mengarelli, Andrea Passananti, Claudio Fanciulli, Maurizio |
author_facet | Bruno, Tiziana Corleone, Giacomo Catena, Valeria Cortile, Clelia De Nicola, Francesca Fabretti, Francesca Gumenyuk, Svitlana Pisani, Francesco Mengarelli, Andrea Passananti, Claudio Fanciulli, Maurizio |
author_sort | Bruno, Tiziana |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9670196 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96701962022-11-18 AATF/Che‐1 localizes to paraspeckles and suppresses R‐loops accumulation and interferon activation in Multiple Myeloma Bruno, Tiziana Corleone, Giacomo Catena, Valeria Cortile, Clelia De Nicola, Francesca Fabretti, Francesca Gumenyuk, Svitlana Pisani, Francesco Mengarelli, Andrea Passananti, Claudio Fanciulli, Maurizio EMBO J Articles 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. John Wiley and Sons Inc. 2022-08-05 /pmc/articles/PMC9670196/ /pubmed/35929179 http://dx.doi.org/10.15252/embj.2021109711 Text en © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Articles Bruno, Tiziana Corleone, Giacomo Catena, Valeria Cortile, Clelia De Nicola, Francesca Fabretti, Francesca Gumenyuk, Svitlana Pisani, Francesco Mengarelli, Andrea Passananti, Claudio Fanciulli, Maurizio AATF/Che‐1 localizes to paraspeckles and suppresses R‐loops accumulation and interferon activation in Multiple Myeloma |
title |
AATF/Che‐1 localizes to paraspeckles and suppresses R‐loops accumulation and interferon activation in Multiple Myeloma |
title_full |
AATF/Che‐1 localizes to paraspeckles and suppresses R‐loops accumulation and interferon activation in Multiple Myeloma |
title_fullStr |
AATF/Che‐1 localizes to paraspeckles and suppresses R‐loops accumulation and interferon activation in Multiple Myeloma |
title_full_unstemmed |
AATF/Che‐1 localizes to paraspeckles and suppresses R‐loops accumulation and interferon activation in Multiple Myeloma |
title_short |
AATF/Che‐1 localizes to paraspeckles and suppresses R‐loops accumulation and interferon activation in Multiple Myeloma |
title_sort | aatf/che‐1 localizes to paraspeckles and suppresses r‐loops accumulation and interferon activation in multiple myeloma |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9670196/ https://www.ncbi.nlm.nih.gov/pubmed/35929179 http://dx.doi.org/10.15252/embj.2021109711 |
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