RNAs anchoring replication complex control initiation and firing of DNA replication

Coordinated initiation of DNA replication is essential to ensure efficient and timely DNA synthesis. Yet the molecular determinants that confer origin selectivity in mammalian cells remain incompletely defined. Herein, we present data demonstrating a pivotal role for RNAs transcribed in the proximity of actively replicating gene loci. We show that RNAs aNChoring ORC1 (ANCORs) to the histone variant H2A.Z facilitate origin firing during DNA replication. This ANCOR-H2A.Z interaction appears to be essential for cells to duplicate their genetic material. Widespread and locus-specific perturbations of these transcripts correlate with anomalous replication patterns and a notable loss of the H2A.Z replicative marker at the origin site. Collectively, we present a previously undescribed RNA-mediated mechanism that is associated with the generation of active replication origins in mammalian cells. Our findings delineate a strategy to modulate the origins of replication in human cells at a local and global level, with potentially broad biomedical implications. The molecular basis of DNA replication origin selectivity in mammalian cells is not fully understood. Here, the authors show that RNAs (ANCORs) anchoring the replication factor ORC1 to the histone variant H2A.Z facilitate DNA replication. Perturbation of this RNA-mediated mechanism alters DNA replication, revealing a strategy to modulate replication origins.

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Publication Details

Journal
Nature Communications
Published
2026-05-27
DOI
https://doi.org/10.1038/s41467-026-73478-2
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

RNAs anchoring replication complex control initiation and firing of DNA replication

Jeannine Gerhardt, Nicholas H Mandel, Lucrezia Rinaldi, Theodore Paniza et al.
Nature Communications
DNA Repair Mechanisms
article

RNAs anchoring replication complex control initiation and firing of DNA replication

Jeannine Gerhardt, Nicholas H Mandel, Lucrezia Rinaldi, Theodore Paniza, Sergei M. Mirkin, Ida Autiero, Annalisa Di Ruscio, Simone Ummarino, Larysa Poluben, Steven P. Balk, Yanzhou Zhang, Alexander K. Ebralidze, Bogdan Budnik, Mahmoud A. Bassal, Johnathan D. Lee, Daniel G. Tenen, Madhura Deshpande, Robert Flaumenhaft, Bon Q. Trinh
article en

Abstract

Coordinated initiation of DNA replication is essential to ensure efficient and timely DNA synthesis. Yet the molecular determinants that confer origin selectivity in mammalian cells remain incompletely defined. Herein, we present data demonstrating a pivotal role for RNAs transcribed in the proximity of actively replicating gene loci. We show that RNAs aNChoring ORC1 (ANCORs) to the histone variant H2A.Z facilitate origin firing during DNA replication. This ANCOR-H2A.Z interaction appears to be essential for cells to duplicate their genetic material. Widespread and locus-specific perturbations of these transcripts correlate with anomalous replication patterns and a notable loss of the H2A.Z replicative marker at the origin site. Collectively, we present a previously undescribed RNA-mediated mechanism that is associated with the generation of active replication origins in mammalian cells. Our findings delineate a strategy to modulate the origins of replication in human cells at a local and global level, with potentially broad biomedical implications. The molecular basis of DNA replication origin selectivity in mammalian cells is not fully understood. Here, the authors show that RNAs (ANCORs) anchoring the replication factor ORC1 to the histone variant H2A.Z facilitate DNA replication. Perturbation of this RNA-mediated mechanism alters DNA replication, revealing a strategy to modulate replication origins.

Nature Communications
Tufts University (US), Beth Israel Deaconess Medical Center (US), Harvard University (US), National University of Singapore (SG), Cornell University (US), Harvard Affiliated Emergency Medicine Residency (US), National University Cancer Institute, Singapore (SG), Dana-Farber/Harvard Cancer Center (US), Institute of Biostructure and Bioimaging (IT), Piedmont University (US), Harvard Stem Cell Institute (US), University of Virginia (US)
National Institutes of Health, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 10%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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