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

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 Rloops 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.

Pathophysiological Role and Diagnostic Potential of R-Loops in Cancer and Beyond

“…In Multiple Myeloma (MM), elevated levels of R-loops and the failure to resolve R-loops can cause the sustained activation of a systemic inflammatory response characterized by the interferon (IFN) gene expression signature, which results in a poor prognosis [ 126 ]. Along with an elevated expression of para-speckle genes, R-loops have been identified to correlate with MM’s progression [ 119 ]. Altogether, unscheduled R-loop accumulation could be used to identify distinct biological properties (heterogeneity) in tumors [ 119 , 124 , 125 ], can guide the monitoring of the severity of disorders [ 25 ], and has a strong prognostic potential.…”

“…Along with an elevated expression of para-speckle genes, R-loops have been identified to correlate with MM’s progression [ 119 ]. Altogether, unscheduled R-loop accumulation could be used to identify distinct biological properties (heterogeneity) in tumors [ 119 , 124 , 125 ], can guide the monitoring of the severity of disorders [ 25 ], and has a strong prognostic potential.…”

HAX1 Is a Novel Binding Partner of Che-1/AATF. Implications in Oxidative Stress Cell Response

“…Che-1 is an RNA polymerase (RNA Pol) I and II interacting protein highly conserved during evolution [40,41]. It is involved in many fundamental cellular processes, such as transcriptional regulation, ribosome biogenesis, cell-cycle and apoptosis control, cellular response to DNA damage and stress, RNA binding and inflammatory response activation [42][43][44][45][46]. At the cellular level, Che-1 predominantly shows a nuclear and nucleolar localization [41].…”

“…In addition, Che-1 shows a protective role in human kidney proximal tubule cells, where this protein has been observed to counteract apoptotic cell death following induced-renal injury by preserving mitochondrial function and reducing oxidative damage [54]. Over the last years, several pieces of evidence indicate that Che-1 serves as a critical regulator in various cancers and promotes tumorigenesis by protecting cancer cells from apoptosis induction, favoring cell proliferation, or promoting cell survival by autophagy [44,[55][56][57][58]. In breast cancer Che-1 is upregulated and its gene silencing leads to stimulation of apoptotic cell death via upregulation of proapoptotic genes and downregulation of ERα, a key factor in breast cancer development [42,59].…”

“…In breast cancer Che-1 is upregulated and its gene silencing leads to stimulation of apoptotic cell death via upregulation of proapoptotic genes and downregulation of ERα, a key factor in breast cancer development [42,59]. Of importance, Bruno and colleagues have recently shown that Che-1 depletion leads to downregulation of HAX1 in Multiple Myeloma [44].…”