Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging.

Xue Hao, Bo Zhao, Qingqing Yan, Mitsutake Yano, Ayumu Matsuoka, Yuan Qi, Liping Liao, Rafal J Zielinski, Hsin-Yao Tang, Andrew V Kossenkov, M Anna Zal, Kavitha Sarma, Rugang Zhang

Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · pubmed

Paper

Abstract

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.

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Research summary

The study identifies the DDX1-XPO1 complex as a mechanism for exporting nuclear R-loops to the cytoplasm, where they activate cGAS-STING to drive the senescence-associated secretory phenotype (SASP) and inflammaging. This is relevant because it elucidates a specific molecular root cause of inflammaging, a key hallmark of aging, and demonstrates that targeting this pathway with KPT-330 can mitigate age-associated inflammation and extend healthspan in a model system.

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