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

Accumulation of R-loops, which are transcriptional by-products, poses a persistent threat to genome integrity and are implicated in accelerated ageing and cancer. PSIP1/LEDGF is a chromatin protein, shown to have histone chaperone activity and interact with transcriptional elongation complex. Here, we demonstrated that PSIP1 interacts with R-loops and with the factors involved in R-loop resolution, including PARP1. Reduced PSIP1 levels in human and mouse cells increase R-loop and DNA damage levels at the PSIP1 binding sites. This increased R-loops and DNA damage was specific at the RNA polymerase II transcription sites, causing local transcriptional arrest and reduced replication rate. In addition, we demonstrate that targeting PSIP1 increases the sensitivity of cancer cells to PARP1 inhibitors and transcription-coupled DNA-damaging agents. Overall, our findings reveal the critical role of PSIP1 in maintaining genome stability by reducing the R-loop burden and DNA damage at the transcriptionally active regions of the genome.