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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\u00a0hybrids can actually\u00a0form as a consequence of replication-born discontinuities such as unprocessed flaps or unligated Okazaki fragments. Strikingly, such \u201cpost-lesion\u201d DNA:RNA hybrids neither detectably contribute to genetic instability, nor disturb gene expression, as opposed to \u201cpre-lesion\u201d hybrids formed upon defective mRNA biogenesis, <jats:italic>e.g<\/jats:italic>., 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.<\/jats:p>","DOI":"10.1038\/s41467-025-57588-x","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T23:10:52Z","timestamp":1741648252000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["DNA lesions can frequently precede DNA:RNA hybrid accumulation"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6180-1926","authenticated-orcid":false,"given":"Rapha\u00ebl M.","family":"Mangione","sequence":"first","affiliation":[]},{"given":"Steven","family":"Pierce","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4660-204X","authenticated-orcid":false,"given":"Myriam","family":"Zheng","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5600-7525","authenticated-orcid":false,"given":"Robert M.","family":"Martin","sequence":"additional","affiliation":[]},{"given":"Coralie","family":"Goncalves","sequence":"additional","affiliation":[]},{"given":"Arun","family":"Kumar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-5645","authenticated-orcid":false,"given":"Sarah","family":"Scaglione","sequence":"additional","affiliation":[]},{"given":"Cristiana","family":"de Sousa Morgado","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3790-1921","authenticated-orcid":false,"given":"Arianna","family":"Penzo","sequence":"additional","affiliation":[]},{"given":"Astrid","family":"Lancrey","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7424-3537","authenticated-orcid":false,"given":"Robert J. 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