MassIVE MSV000097565

Partial Public PXD062738

Targeting XPO1/DDX1-mediated nuclear export of R-loops in inflammaging

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Description

R-loops are three-stranded nucleic acids containing DNA-RNA hybrid and a third displaced ssDNA and are widely distributed across the genome. Dysregulation in R-loop dynamics cause DNA damage and genome instability. Although its role has been extensively investigated in various pathological processes, whether R-loops are perturbed during senescence and tissue aging remains unclear. Here we obverse a global decline in R-loop stalling across the genome during senescence. While R-loops in nuclear were dramatically decreased, we detected their significant accumulation in the cytoplasm in senescent cells. We identify their source as nuclear R-loops with a specific enrichment in alpha-satellites, a subset of repetitive elements. Notably, these cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCF) to induce cGAS-STING innate immune response, and this nucleocytoplasmic transport is dependent on exportin 1 (XPO1)/DEAD-Box helicase 1 (DDX1) complex. Targeting R-loop nuclear export by XPO1 inhibitor Selinexor (KPT-330) suppresses the inflammatory response in senescent cells and relieves inflammaging in aged mice. In summary, our findings linked aberrant accumulation of cytoplasmic R-loops to inflammaging, rendering their nucleocytoplasmic transport process an ideal target for suppressing inflammaging. [doi:10.25345/C5F18ST06] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: R-loops ; XPO1 ; DDX1 ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Rugang Zhang, MS Anderson Cancer Center, United States
Submitting User: tangh
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