PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity

Abstract Accumulation of R-loops, which are transcriptional by-products, poses a persistent threat to genome integrity. Here we show that PSIP1, a protein involved in transcriptional elongation, interacts with R-loops and multiple proteins involved in R-loop homeostasis, including PARP1. We demonstrate the role of PSIP1 in preventing genome instability by reducing the R-loop level and DNA damage at the transcriptionally active regions of the genome. We show that PSIP1 depletion leads to R-loop accumulation, which causes local transcriptional arrest and transcription-replication conflict leading to DNA damage. Furthermore, PSIP1 depletion increases the sensitises cancer cells to DNA-damaging agents that induce R-loop-induced DNA damage. These findings provide novel insights into the mechanism through which genome integrity is maintained at the site of transcription.