ORC1 binds to cis-transcribed RNAs for efficient activation of replication origins

Aina Maria Mas, Enrique Goñi, Igor Ruiz de los Mozos, Aida Arcas, Luisa Statello, Jovanna González, Lorea Blázquez, Wei Ting Chelsea Lee, Dipika Gupta, Álvaro Sejas, Shoko Hoshina, Alexandros Armaos, Gian Gaetano Tartaglia, Shou Waga, Jernej Ule, Eli Rothenberg, María Gómez and Maite Huarte ()
Additional contact information
Aina Maria Mas: University of Navarra
Enrique Goñi: University of Navarra
Igor Ruiz de los Mozos: University of Navarra
Aida Arcas: University of Navarra
Luisa Statello: University of Navarra
Jovanna González: University of Navarra
Lorea Blázquez: The Francis Crick Institute
Wei Ting Chelsea Lee: New York University School of Medicine
Dipika Gupta: New York University School of Medicine
Álvaro Sejas: University of Navarra
Shoko Hoshina: Japan Women’s University
Alexandros Armaos: Istituto Italiano di Tecnologia
Gian Gaetano Tartaglia: Istituto Italiano di Tecnologia
Shou Waga: Japan Women’s University
Jernej Ule: The Francis Crick Institute
Eli Rothenberg: New York University School of Medicine
María Gómez: Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid (CSIC/UAM)
Maite Huarte: University of Navarra

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Cells 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.

Date: 2023
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DOI: 10.1038/s41467-023-40105-3

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