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 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. Synopsis: Che‐1/AATF (Che‐1) is a nuclear protein involved in cellular stress response and neoplastic transformation in Multiple Myeloma. Here, Che‐1 is identified as a component of paraspeckles and a key factor in cell stress resolution in Multiple Myeloma.Che‐1 interacts with NEAT1 lncRNA and localizes to nuclear paraspeckles.Che‐1 and NEAT1 prevent ER‐stress‐dependent R‐loop accumulation in MM cells.Che‐1‐mediated R‐loop suppression prevents interferon (IFN) response activation.Elevated R‐loops levels and expression of paraspeckle genes are associated with MM progression in patient tissues. [ABSTRACT FROM AUTHOR]