Endogenous DNA damage at sites of terminated transcripts

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, Matthew B. Cooke, Yin Zhai, David Bates, Lei Li, P. J. Hastings, Irina Artsimovitch, Christophe Herman, Patrick M. Sung, Kyle M. Miller () and Susan M. Rosenberg ()
Additional contact information
Jingjing Liu: Baylor College of Medicine
Jullian O. Perren: University of Texas at Austin
Cody M. Rogers: University of Texas Health Science Center at San Antonio
Sadeieh Nimer: Baylor College of Medicine
Alice X. Wen: Baylor College of Medicine
Jennifer A. Halliday: Baylor College of Medicine
Devon M. Fitzgerald: Baylor College of Medicine
Qian Mei: Baylor College of Medicine
Ralf B. Nehring: Baylor College of Medicine
Mary Crum: Baylor College of Medicine
Stanislav G. Kozmin: Baylor College of Medicine
Jun Xia: Baylor College of Medicine
Matthew B. Cooke: Baylor College of Medicine
Yin Zhai: Baylor College of Medicine
David Bates: Baylor College of Medicine
Lei Li: University of Texas MD Anderson Cancer Center
P. J. Hastings: Baylor College of Medicine
Irina Artsimovitch: Ohio State University
Christophe Herman: Baylor College of Medicine
Patrick M. Sung: University of Texas Health Science Center at San Antonio
Kyle M. Miller: Baylor College of Medicine
Susan M. Rosenberg: Baylor College of Medicine

Nature, 2025, vol. 640, issue 8057, 240-248

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08578-4

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