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While the effects of R-loops on health and disease are well established, there is still an incomplete understanding of the cellular processes responsible for their removal from eukaryotic genomes. Here, we show that a core regulator of chromosome architecture \u2014the Smc5\/6 complex\u2014 plays a crucial role in the removal of R-loop structures formed during gene transcription. Consistent with this, budding yeast mutants defective in the Smc5\/6 complex and enzymes involved in R-loop resolution show strong synthetic interactions and accumulate high levels of RNA-DNA hybrid structures in their chromosomes. Importantly, we demonstrate that the Smc5\/6 complex acts on specific types of RNA-DNA hybrid structures in vivo and promotes R-loop degradation by the RNase H2 enzyme in vitro. Collectively, our results reveal a crucial role for the Smc5\/6 complex in the removal of toxic R-loops formed at highly transcribed genes and telomeres.<\/jats:p>","DOI":"10.7554\/elife.96626","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T08:00:08Z","timestamp":1728979208000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.96626","source":"Crossref","is-referenced-by-count":8,"title":["The Smc5\/6 complex counteracts R-loop formation at highly transcribed genes in cooperation with RNase H2"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9732-1446","authenticated-orcid":true,"given":"Shamayita","family":"Roy","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03c4mmv16","id-type":"ROR","asserted-by":"publisher"}],"name":"Ottawa Institute of Systems Biology, Department of Cellular and Molecular Medicine, University of Ottawa","place":["Ottawa, 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