R-loop dependent promoter-proximal termination ensures genome stability.

The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions 1,2 . Here, we identify SOSS-INTAC as a stable association of the genome stability regulator Sensor of Single-stranded DNA (ssDNA) (SOSS) 3 and the transcription regulator Integrator-PP2A (INTAC) 4-6 . Via SSB1-mediated ssDNA recognition, SOSS-INTAC stimulates promoter-proximal termination of transcription and attenuates paused Pol II-associated R-loops to prevent R-loop-induced genome instability. SOSS-INTAC-dependent attenuation of R-loops is enhanced by SSB1's ability to form liquid-like condensates. Deletion of, or introduction of cancer-associated mutations within its intrinsically disordered region (IDR), leads to pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS-INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation to ensure genome stability.