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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.

Origin recognition complex (ORC) binds to replication origins in eukaryotic DNAs and plays an important role in replication. Although yeast ORC is known to sequence-specifically bind to a replication origin, how human ORC recognizes a replication origin remains unknown. Previous genome-wide studies revealed that guanine (G)-rich sequences, potentially forming G-quadruplex (G4) structures, are present in most replication origins in human cells. We previously suggested that the region comprising residues 413–511 of human ORC subunit 1, hORC1413–511, binds preferentially to G-rich DNAs, which form a G4 structure in the absence of hORC1413–511. Here, we investigated the interaction of hORC1413-511 with various G-rich DNAs derived from human c-myc promoter and telomere regions. Fluorescence anisotropy revealed that hORC1413–511 binds preferentially to DNAs that have G4 structures over ones having double-stranded structures. Importantly, circular dichroism (CD) and nuclear magnetic resonance (NMR) showed that those G-rich DNAs retain the G4 structures even after binding with hORC1413–511. NMR chemical shift perturbation analyses revealed that the external G-tetrad planes of the G4 structures are the primary binding sites for hORC1413–511. The present study suggests that human ORC1 may recognize replication origins through the G4 structure.

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. We propose that fluctuating concentrations of RNA during the cell cycle may play a sequential role in controlling origins through interaction with this flexible region of ORC1. Our results unveil a novel non-coding function of RNA as a dynamic component of the chromatin, orchestrating the activation of replication origins.Competing Interest StatementThe authors have declared no competing interest.

A global increase in severe group A Streptococcus (GAS) infections has been reported following the COVID-19 pandemic, but data from Asia remain limited. We examined epidemiology and clinical characteristics of severe paediatric GAS infections across 86 Japanese hospitals, focusing on patients under 18 years of age, hospitalized between 1 January 2019 and 31 March 2024. Severe GAS infection was defined by the isolation of GAS from sterile sites, or from non-sterile sites under specific conditions, such as streptococcal toxic shock syndrome (STSS). A total of 83 cases were analysed. Cases increased from the summer of 2023, exceeding pre-pandemic levels. The median age was 4 (interquartile range: 1–8) years, with the highest number among 1-year-olds. No cases were reported in Hokkaido, northern Japan. Only 6% (5/83) of the cases had preceding GAS pharyngitis. Pneumonia was the most prevalent diagnosis (25%), with 76% of these cases being complicated by empyema, often necessitating intensive care or surgical intervention. Only 17% (14/83) of cases were reported as STSS in Japan’s national surveillance system. This study represents the first multicentre nationwide hospital-based investigation of severe paediatric GAS infections in Japan, identifying the recent increase in cases, thereby highlighting limitations of current STSS-based surveillance.