Long noncoding RNA Lnc530 localizes on R-loops and regulates R-loop formation and genomic stability in mouse embryonic stem cells.

Abstract

Embryonic stem cells (ESCs) are superior to differentiated cells to maintain genome stability, but the underlying mechanisms remain largely elusive. R-loops are constantly formed during transcription and are inducers of DNA damage if not resolved. Here we report that mouse ESCs (mESCs) can efficiently prevent unscheduled R-loop formation, and a long noncoding RNA Lnc530 plays regulatory role. Lnc530 is expressed in mESCs and localizes on R-loops. Depletion of Lnc530 in mESCs causes R-loop accumulation and DNA damage, whereas forced expression of Lnc530 in differentiated cells suppresses the R-loop formation. Mechanistically, Lnc530 associates with DDX5 and TDP-43 in an inter-dependent manner on R-loops. Formation of Lnc530-DDX5-TDP-43 complex substantially increases the local protein levels of DDX5 and TDP-43, both of which play critical roles in R-loop regulation. This study uncovers an efficient strategy to prevent R-loop accumulation and preserve genomic stability in mESCs and possibly other stem cell types.