DNA double-strand breaks (DSBs) represent a lethal form of DNA damage that can trigger cell death or initiate oncogenesis. The activity of RNA polymerase II (RNAPII) at the break site is required for efficient DSB repair. However, the regulatory mechanisms governing the transcription cycle at DSBs are not well understood. Here, we show that Integrator complex subunit 6 (INTS6) associates with the heterotrimeric sensor of ssDNA (SOSS1) complex (comprising INTS3, INIP and hSSB1) to form the tetrameric SOSS1 complex. INTS6 binds to DNA:RNA hybrids and promotes Protein Phosphatase 2A (PP2A) recruitment to DSBs, facilitating the dephosphorylation of RNAPII. Furthermore, INTS6 prevents the accumulation of damage-associated RNA transcripts (DARTs) and the stabilization of DNA:RNA hybrids at DSB sites. INTS6 interacts with and promotes the recruitment of senataxin (SETX) to DSBs, facilitating the resolution of DNA:RNA hybrids/R-loops. Our results underscore the significance of the tetrameric SOSS1 complex in the autoregulation of DNA:RNA hybrids and efficient DNA repair.

• MeSH
• DNA-Binding Proteins metabolism   MeSH
• DNA Helicases metabolism   genetics   MeSH
• DNA * metabolism   chemistry   MeSH
• DNA Breaks, Double-Stranded * MeSH
• Phosphorylation MeSH
• Homeostasis genetics   MeSH
• Humans MeSH
• DNA Repair * MeSH
• Protein Phosphatase 2 metabolism   genetics   MeSH
• R-Loop Structures MeSH
• RNA Helicases metabolism   genetics   MeSH
• RNA Polymerase II * metabolism   MeSH
• RNA * metabolism   genetics   chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA-Binding Proteins MeSH
• DNA Helicases MeSH
• DNA * MeSH
• Protein Phosphatase 2 MeSH
• RNA Helicases MeSH
• RNA Polymerase II * MeSH
• RNA * MeSH