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

• Published in: Nature communications Vol. 14; no. 1; pp. 4447 - 19
• Main Authors: Mas, Aina Maria, Goñi, Enrique, Ruiz de los Mozos, Igor, Arcas, Aida, Statello, Luisa, González, Jovanna, Blázquez, Lorea, Lee, Wei Ting Chelsea, Gupta, Dipika, Sejas, Álvaro, Hoshina, Shoko, Armaos, Alexandros, Tartaglia, Gian Gaetano, Waga, Shou, Ule, Jernej, Rothenberg, Eli, Gómez, María, Huarte, Maite
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 14/63; 38/15; 38/22; 45; 45/90; 45/91; 631/337; 631/337/151/2355; 631/337/384; Animals; Binding; Cell activation; Chromatin; Genes; Genomes; Humanities and Social Sciences; Humans; Mammals; Molecular interactions; multidisciplinary; Origin Recognition Complex; Origins; Phase separation; Phosphorylation; Recognition; Replication; Replication Origin; Replication origins; Ribonucleic acid; RNA; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40105-3

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. Here the authors describe that the human origin recognition complex subunit 1 (ORC1) binds to RNAs transcribed from genes with origins of replication at their TSS impacting origin activation.