DNA lesions can frequently precede DNA:RNA hybrid accumulation

Raphaël M. Mangione, Steven Pierce, Myriam Zheng, Robert M. Martin, Coralie Goncalves, Arun Kumar, Sarah Scaglione, Cristiana Sousa Morgado, Arianna Penzo, Astrid Lancrey, Robert J. D. Reid, Ophélie Lautier, Pierre-Henri Gaillard, Peter C. Stirling, Sérgio F. Almeida, Rodney Rothstein and Benoit Palancade ()
Additional contact information
Raphaël M. Mangione: Université Paris Cité, CNRS, Institut Jacques Monod
Steven Pierce: Columbia University Irving Medical Center
Myriam Zheng: Université Paris Cité, CNRS, Institut Jacques Monod
Robert M. Martin: GIMM—Gulbenkian Institute for Molecular Medicine
Coralie Goncalves: Université Paris Cité, CNRS, Institut Jacques Monod
Arun Kumar: BC Cancer
Sarah Scaglione: Aix Marseille Université
Cristiana Sousa Morgado: GIMM—Gulbenkian Institute for Molecular Medicine
Arianna Penzo: Université Paris Cité, CNRS, Institut Jacques Monod
Astrid Lancrey: Université Paris Cité, CNRS, Institut Jacques Monod
Robert J. D. Reid: Columbia University Irving Medical Center
Ophélie Lautier: Université Paris Cité, CNRS, Institut Jacques Monod
Pierre-Henri Gaillard: Aix Marseille Université
Peter C. Stirling: BC Cancer
Sérgio F. Almeida: GIMM—Gulbenkian Institute for Molecular Medicine
Rodney Rothstein: Columbia University Irving Medical Center
Benoit Palancade: Université Paris Cité, CNRS, Institut Jacques Monod

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract While DNA:RNA hybrids contribute to multiple genomic transactions, their unscheduled formation is a recognized source of DNA lesions. Here, through a suite of systematic screens, we rather observed that a wide range of yeast mutant situations primarily triggering DNA damage actually leads to hybrid accumulation. Focusing on Okazaki fragment processing, we establish that genic hybrids can actually form as a consequence of replication-born discontinuities such as unprocessed flaps or unligated Okazaki fragments. Strikingly, such “post-lesion” DNA:RNA hybrids neither detectably contribute to genetic instability, nor disturb gene expression, as opposed to “pre-lesion” hybrids formed upon defective mRNA biogenesis, e.g., in THO complex mutants. Post-lesion hybrids similarly arise in distinct genomic instability situations, triggered by pharmacological or genetic manipulation of DNA-dependent processes, both in yeast and human cells. Altogether, our data establish that the accumulation of transcription-born DNA:RNA hybrids can occur as a consequence of various types of natural or pathological DNA lesions, yet do not necessarily aggravate their genotoxicity.

Date: 2025
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DOI: 10.1038/s41467-025-57588-x

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