DNA lesions can frequently precede DNA:RNA hybrid accumulation

  • Nat Commun. 2025 Mar 10;16(1):2401. doi: 10.1038/s41467-025-57588-x.
Raphaël M Mangione  1 ,  Steven Pierce  #  2 ,  Myriam Zheng  #  1  2 ,  Robert M Martin  #  3  4 ,  Coralie Goncalves  1 ,  Arun Kumar  5  6 ,  Sarah Scaglione  7 ,  Cristiana de Sousa Morgado  3  4 ,  Arianna Penzo  1 ,  Astrid Lancrey  1 ,  Robert J D Reid  2 ,  Ophélie Lautier  1 ,  Pierre-Henri Gaillard  7 ,  Peter C Stirling  5  6 ,  Sérgio F de Almeida  3  4 ,  Rodney Rothstein  2 ,  Benoit Palancade  8
Affiliations
  • 1. Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France.
  • 2. Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA.
  • 3. GIMM-Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal.
  • 4. Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
  • 5. Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada.
  • 6. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
  • 7. Centre de Recherche en Cancérologie de Marseille (CRCM), U1068 Inserm, UMR7258 CNRS, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France.
  • 8. Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France. [email protected].
  • # Contributed equally.
PMID: 40064914 DOI: 10.1038/s41467-025-57588-x
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.

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