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, molecular mechanism describing how replication initiation is coordinated in eukaryotic cells is not completely understood. Herein, we present data demonstrating a novel feature of RNAs transcribed in the proximity of actively replicating gene loci. We show that RNAs aNChoring ORC1 (ANCORs) to the histone variant H2A.Z are licensors of the DNA replication process. This ANCOR-H2A.Z interaction is essential for cells to initiate duplication of 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 eukaryotic 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.