TOP1 and R-loops facilitate transcriptional DSBs at hypertranscribed cancer driver genes

Osama Hidmi, Sara Oster, Jonathan Monin, Rami I. Aqeilan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageAmerican English
Article number109082
JournaliScience
Volume27
Issue number3
DOIs
StatePublished - 15 Mar 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Keywords

  • Biological sciences
  • Cancer
  • Molecular mechanism of gene regulation
  • Transcriptomics

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