PT  - JOURNAL ARTICLE
AU  - Tiziana Bruno
AU  - Giacomo Corleone
AU  - Clelia Cortile
AU  - Francesca De Nicola
AU  - Valeria Catena
AU  - Francesca Fabretti
AU  - Svitlana Gumenyuk
AU  - Francesco Pisani
AU  - Andrea Mengarelli
AU  - Claudio Passananti
AU  - Maurizio Fanciulli
TI  - AATF/Che-1, a new component of paraspeckles, controls R-loops formation and Interferon activation in Multiple Myeloma
AID  - 10.1101/2021.08.04.455054
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.04.455054
4099  - http://biorxiv.org/content/early/2021/08/05/2021.08.04.455054.short
4100  - http://biorxiv.org/content/early/2021/08/05/2021.08.04.455054.full
AB  - Multiple myeloma (MM) is a hematological neoplasm of plasma cells characterized by abnormal production of immunoglobulins. Che-1/AATF (Che-1) is an RNA binding protein involved in transcription regulation and is highly expressed in this malignancy. Here we experimentally show that Che-1 interacts with paraspeckle components, including the lncRNA NEAT1_2 (NEAT1), which serves as the seed for the maintenance of these structures. Che-1 and NEAT1 localize on R-loops, three-stranded RNA:DNA hybrids structures involved in DNA transcription and repair. Depletion of Che-1 produces a marked accumulation of RNA:DNA hybrids sustaining activation of a systemic inflammatory response. We provide evidence that high levels of Unfolded Protein Response (UPR) in MM cells induces RNA:DNA hybrids and an interferon (IFN) gene signature. We found that MM patients exhibit elevated R-loops levels and paraspeckle genes mRNAs increase linearly to MM progression. Strikingly, patients showing elevated IFN genes signature are associated with a marked poor prognosis. Overall, these findings delineate that elevated R-loops accumulation and inflammatory signaling may contribute to MM progression and that Che-1/NEAT1 plays an essential role in maintaining R-loops homeostasis by preventing excessive inflammatory signaling.Competing Interest StatementThe authors have declared no competing interest.