2. Academic Validation
  3. DNA lesions can frequently precede DNA:RNA hybrid accumulation

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

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. benoit.palancade@ijm.fr.
  • # 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.

Figures
Products