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

Abstract The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions 1,2 . Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS) 3 and the transcription regulator Integrator-PP2A (INTAC) 4–6 . Through SSB1-mediated recognition of single-stranded DNA, SOSS–INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS–INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a 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 and ensure genome stability.