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.