R-loop dependent promoter-proximal termination ensures genome stability [ATAC-seq]

Precise regulation of transcription is essential to maintain genome integrity, yet key mechanisms coordinating transcription, genome stability and downstream cellular functions remain incomplete. Here we report the identification of SOSS-INTAC, a stable association of the genome stability regulator Sensor of Single-stranded DNA (ssDNA) (SOSS) complex and transcription regulator Integrator-PP2A (INTAC). Via SSB1-mediated ssDNA recognition at its targets, SOSS-INTAC stimulates early termination of transcription and thus attenuates paused Pol II-induced formation of R-loops to prevent its aberrant accumulation that has the risk of increasing chromatin accessibility and compromising genome stability. SOSS-INTAC-mediated attenuation of R-loops is greatly enhanced by SSB1's unique property of forming liquid-like condensates. In contrast, preventing SSB1 condensation through deletion or cancer-associated mutation within its intrinsically disordered region (IDR) leads to pervasive accumulation of R-loops at a genome-wide level. Thus, our study highlights the genomic surveillance function of SOSS-INTAC that enables timely transcriptional termination to constrain aberrant R-loop accumulation and ensure genomic stability. ATAC-seq with 2 biological replicates in DLD-1 cells.