DNA R-Loops in the Cytoplasm Drive Senescent Cell Inflammatory Signaling
The accumulation of senescent cells in aged tissues is harmful because these cells generate a potent mix of inflammatory signals known as the senescence-associated secretory phenotype, disruptive to tissue structure and function when sustained over the long term. Researchers are interested in finding ways to selectively suppress this signaling, which involves better understanding the mechanisms that promote it. Here, researchers find a way in which senescent cells provoke the well studied cGAS-STING inflammatory pathway, a system that reacts to mislocalized or foreign DNA in the cell cytoplasm, via export of R-loop DNA structures from the cell nucleus.
Cellular senescence contributes to inflammaging in part through the senescence-associated secretory phenotype (SASP). R-loops, three-stranded nucleic acid structures, contribute to innate immune response in cancers; however, the role of R-loops in senescence and inflammaging remains largely unknown. Here we show that nuclear-derived cytoplasmic R-loops promote the SASP and inflammaging. We detect an accumulation of nuclear-derived R-loops in the cytoplasm of senescent cells with an enrichment in alpha-satellite repeats. These cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCFs) and activate the cGAS-STING innate immune pathway to drive the SASP.
We identify the exportin-1 (XPO1)-DEAD-Box helicase 1 (DDX1) complex as essential for the nuclear export of R-loops and their subsequent localization into CCFs. Inhibition of XPO1 with KPT-330 suppresses nuclear R-loop export and its localization into CCFs, attenuates the SASP, mitigates age-associated inflammation and extends healthspan. These findings reveal nuclear export of R-loops as a potential target for suppressing age-associated inflammation.