XPF interacts with TOP2B for R-loop processing and DNA looping on actively transcribed genes


  • G. Chatzinikolaou
  • K. Stratigi
  • A. Siametis
  • E. Goulielmaki
  • A. Akalestou-Clocher
  • I. Tsamardinos
  • P. Topalis
  • C. Austin
  • B.A.M. Bouwman
  • N. Crosetto
  • J. Altmüller
  • G.A. Garinis


  • Science Advances


  • Sci Adv 9 (45): eadi2095


  • Co-transcriptional RNA-DNA hybrids can not only cause DNA damage threatening genome integrity but also regulate gene activity in a mechanism that remains unclear. Here, we show that the nucleotide excision repair factor XPF interacts with the insulator binding protein CTCF and the cohesin subunits SMC1A and SMC3, leading to R-loop-dependent DNA looping upon transcription activation. To facilitate R-loop processing, XPF interacts and recruits with TOP2B on active gene promoters, leading to double-strand break accumulation and the activation of a DNA damage response. Abrogation of TOP2B leads to the diminished recruitment of XPF, CTCF, and the cohesin subunits to promoters of actively transcribed genes and R-loops and the concurrent impairment of CTCF-mediated DNA looping. Together, our findings disclose an essential role for XPF with TOP2B and the CTCF/cohesin complex in R-loop processing for transcription activation with important ramifications for DNA repair-deficient syndromes associated with transcription-associated DNA damage.