Hidmi Osama, Oster Sara, Monin Jonathan, Aqeilan Rami I
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Cyprus Cancer Research Institute (CCRI), Nicosia, Cyprus.
iScience. 2024 Feb 1;27(3):109082. doi: 10.1016/j.isci.2024.109082. eCollection 2024 Mar 15.
DNA double-stranded breaks (DSBs) pose a significant threat to genomic integrity, and their generation during essential cellular processes like transcription remains poorly understood. In this study, we employ several techniques to map DSBs, R-loops, and topoisomerase 1 cleavage complex (TOP1cc) to comprehensively investigate the interplay between transcription, DSBs, topoisomerase 1 (TOP1), and R-loops. Our findings reveal the presence of DSBs at highly expressed genes enriched with TOP1 and R-loops. Remarkably, transcription-associated DSBs at these loci are significantly reduced upon depletion of R-loops and TOP1, uncovering the pivotal roles of TOP1 and R-loops in transcriptional DSB formation. By elucidating the intricate interplay between TOP1cc trapping, R-loops, and DSBs, our study provides insights into the mechanisms underlying transcription-associated genomic instability. Moreover, we establish a link between transcriptional DSBs and early molecular changes driving cancer development, highlighting the distinct etiology and molecular characteristics of driver mutations compared to passenger mutations.
DNA双链断裂（DSBs）对基因组完整性构成重大威胁，而在转录等基本细胞过程中其产生机制仍知之甚少。在本研究中，我们采用多种技术来绘制DSBs、R环和拓扑异构酶1切割复合物（TOP1cc）的图谱，以全面研究转录、DSBs、拓扑异构酶1（TOP1）和R环之间的相互作用。我们的研究结果揭示了在富含TOP1和R环的高表达基因处存在DSBs。值得注意的是，当R环和TOP1缺失时，这些位点与转录相关的DSBs显著减少，揭示了TOP1和R环在转录性DSB形成中的关键作用。通过阐明TOP1cc捕获、R环和DSBs之间的复杂相互作用，我们的研究为转录相关基因组不稳定的潜在机制提供了见解。此外，我们建立了转录性DSBs与驱动癌症发展的早期分子变化之间的联系，突出了驱动突变与乘客突变相比独特的病因和分子特征。
