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

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.

Citation

Georgia Chatzinikolaou, Kalliopi Stratigi, Athanasios Siametis, Evi Goulielmaki, Alexia Akalestou-Clocher, Ioannis Tsamardinos, Pantelis Topalis, Caroline Austin, Britta A M Bouwman, Nicola Crosetto, Janine Altmüller, George A Garinis. XPF interacts with TOP2B for R-loop processing and DNA looping on actively transcribed genes. Science advances. 2023 Nov 10;9(45):eadi2095

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PMID: 37939182

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