Dual Processing of R-Loops and Topoisomerase I Induces Transcription-Dependent DNA Double-Strand Breaks

作者：Agnese Cristini, Giulia Ricci, Sébastien Britton, Simona Salimbeni, Shar-yin N. Huang, Jessica Marinello, Patrick Calsou, Yves Pommier, Gilles Favre, Giovanni Capranico, Natalia Gromak, Olivier Sordet · 发表于：Cell Reports · 年份：2019 · DOI：10.1016/j.celrep.2019.08.041 · 被引用次数：171 · 研究领域：Cancer therapeutics and mechanisms、DNA Repair Mechanisms、DNA and Nucleic Acid Chemistry

Although accumulation of DNA damage and genomic instability in resting cells can cause neurodegenerative disorders, our understanding of how transcription produces DNA double-strand breaks (DSBs) is limited. Transcription-blocking topoisomerase I cleavage complexes (TOP1ccs) are frequent events that prime DSB production in non-replicating cells. Here, we report a mechanism of their formation by showing that they arise from two nearby single-strand breaks (SSBs) on opposing DNA strands: one SSB from the removal of transcription-blocking TOP1ccs by the TDP1 pathway and the other from the cleavage of R-loops by endonucleases, including XPF, XPG, and FEN1. Genetic defects in TOP1cc removal (TDP1, PNKP, and XRCC1) or in the resolution of R-loops (SETX) enhance DSB formation and prevent their repair. Such deficiencies cause neurological disorders. Owing to the high frequency of TOP1cc trapping and the widespread distribution of R-loops, these persistent transcriptional DSBs could accumulate over time in neuronal cells, contributing to the neurodegenerative diseases.