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Endogenous DNA damage at sites of terminated transcripts

Author

Listed:
  • Jingjing Liu

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Jullian O. Perren

    (University of Texas at Austin
    Emory University)

  • Cody M. Rogers

    (University of Texas Health Science Center at San Antonio)

  • Sadeieh Nimer

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Alice X. Wen

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Jennifer A. Halliday

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Devon M. Fitzgerald

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Qian Mei

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Ralf B. Nehring

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Mary Crum

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Stanislav G. Kozmin

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Jun Xia

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Matthew B. Cooke

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Yin Zhai

    (Baylor College of Medicine
    Baylor College of Medicine)

  • David Bates

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Lei Li

    (University of Texas MD Anderson Cancer Center)

  • P. J. Hastings

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Irina Artsimovitch

    (Ohio State University)

  • Christophe Herman

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Patrick M. Sung

    (University of Texas Health Science Center at San Antonio)

  • Kyle M. Miller

    (Baylor College of Medicine
    University of Texas at Austin
    Emory University)

  • Susan M. Rosenberg

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

Abstract

DNA damage promotes mutations that fuel cancer, ageing and neurodegenerative diseases1–3, but surprisingly, the causes and types of damage remain largely unknown. There are three identified mechanisms that damage DNA during transcription: collision of RNA polymerase (RNAP) with the DNA-replication machinery head-on and co-directionally4–6, and R-loop-induced DNA breakage7–10. Here we identify novel DNA damage reaction intermediates11,12 and uncover a fourth transcription-related source of DNA damage: endogenous DNA damage at sites of terminated transcripts. We engineered proteins to capture single-stranded DNA (ssDNA) ends with 3′ polarity in bacterial and human cells. In Escherichia coli, spontaneous 3′-ssDNA-end foci were unexpectedly frequent, at one or more per cell division, and arose via two identifiable pathways, both of which were dependent on DNA replication. A pathway associated with double-strand breaks was suppressed by overexpression of replicative DNA polymerase (pol) III, suggesting competition between pol III and DNA damage-promoting proteins. Mapping of recurrent 3′-ssDNA-ends identified distinct 3′-ssDNA-end-hotspots, mostly unrelated to double-strand breaks, next to the 5′-CCTTTTTT transcription-terminator-like sequence. These 3′-ssDNA-termini coincide with RNA 3′-termini identified by DirectRNA sequencing13 or simultaneous 5′ and 3′ end RNA sequencing (SEnd-seq)14 and were prevented by a mutant RNAP that reads through terminators. Our findings reveal that transcription termination or pausing can promote DNA damage and subsequent genomic instability.

Suggested Citation

  • Jingjing Liu & Jullian O. Perren & Cody M. Rogers & Sadeieh Nimer & Alice X. Wen & Jennifer A. Halliday & Devon M. Fitzgerald & Qian Mei & Ralf B. Nehring & Mary Crum & Stanislav G. Kozmin & Jun Xia &, 2025. "Endogenous DNA damage at sites of terminated transcripts," Nature, Nature, vol. 640(8057), pages 240-248, April.
  • Handle: RePEc:nat:nature:v:640:y:2025:i:8057:d:10.1038_s41586-024-08578-4
    DOI: 10.1038/s41586-024-08578-4
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