SFPQ protects DNA repeat stability by recruiting histone H3.3 chaperon activity to R-loop structures [ChIP-seq]

R-loops are atypical, three-stranded nucleic acid structures that contain a stretch of RNA:DNA hybrids and an unpaired single stranded DNA loop. R-loops control physiologically processes, however when unscheduled or persistent they drive genome instability by creating conflicts with transcription and replication. The human genome is composed of up to 75% of repetitive sequence elements that can also hold transcriptional activity. Thus R-loop surveillance at repetitive elements is central for the maintenance of genome integrity. Here we show 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, uses its RNA-recognition motif (RRM) domains to bind chromatin containing R-loops and uses its proline-rich (P) domain to recruit the histone H3.3 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 incorporations, replication stress mediated DNA damage in repeat elements resulting and centromere defects resulting the formation of cytoplasmatic DNA species that activate the cGAS/STING pathway and innate immunity.