Mas, Aina MariaGoñi, EnriqueRuiz de Los Mozos, IgorArcas Mantas, AidaStatello, LuisaGonzález, JovannaBlázquez, LoreaLee, Wei Ting ChelseaGupta, DipikaSejas, ÁlvaroHoshina, ShokoArmaos, Alexandros, 1989-Tartaglia, Gian GaetanoWaga, ShouUle, JernejRothenberg, EliGómez, MaríaHuarte, Maite2023-11-062023-11-062023Mas AM, Goñi E, Ruiz de Los Mozos I, Arcas A, Statello L, González J, Blázquez L, Lee WTC, Gupta D, Sejas Á, Hoshina S, Armaos A, Tartaglia GG, Waga S, Ule J, Rothenberg E, Gómez M, Huarte M. ORC1 binds to cis-transcribed RNAs for efficient activation of replication origins. Nat Commun. 2023 Jul 24;14(1):4447. DOI: 10.1038/s41467-023-40105-32041-1723http://hdl.handle.net/10230/58211Cells must coordinate the activation of thousands of replication origins dispersed throughout their genome. Active transcription is known to favor the formation of mammalian origins, although the role that RNA plays in this process remains unclear. We show that the ORC1 subunit of the human Origin Recognition Complex interacts with RNAs transcribed from genes with origins in their transcription start sites (TSSs), displaying a positive correlation between RNA binding and origin activity. RNA depletion, or the use of ORC1 RNA-binding mutant, result in inefficient activation of proximal origins, linked to impaired ORC1 chromatin release. ORC1 RNA binding activity resides in its intrinsically disordered region, involved in intra- and inter-molecular interactions, regulation by phosphorylation, and phase-separation. We show that RNA binding favors ORC1 chromatin release, by regulating its phosphorylation and subsequent degradation. Our results unveil a non-coding function of RNA as a dynamic component of the chromatin, orchestrating the activation of replication origins.application/pdfeng© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-023-40105-3Molecular biologyNon-coding RNAsOrigin firinginfo:eu-repo/semantics/openAccess