SFPQ Directs Histone H3.3 Deposition to R-Loops in DNA Repeats to Protect Genome Stability

R-loops are three-stranded nucleic acid structures that contain an RNA:DNA hybrid duplex and an unpaired single stranded DNA loop. Unscheduled or persistent R-loops drive genome instability by creating conflicts with transcription and replication. Up to 75% of the human genome comprises repetitive DNA elements that can engage in R-loop formation. We demonstrate that the RNA binding protein SFPQ suppresses R-loop mediated replication stress and DNA damage at repeat elements such as telomeres, (peri)-centromeres, LINE-1 and SINE elements. SFPQ shows in-vitro R-loop binding activity, binds to chromatin containing R-loops and recruits the histone H3.3 specific chaperon DAXX to maintain a correct nucleosome template that antagonizes R-loop formation. Loss of SFPQ results in DAXX delocalization from repeat elements, reduction of histone H3.3 incorporation, replication stress mediated genome instability and the formation of cytoplasmatic DNA species, which activate innate immunity pathways via the cGAS/STING pathway resulting improved sarcoma patient survival.