Orc5 induces large-scale chromatin decondensation in a GCN5-dependent manner

In eukaryotes, origin recognition complex (ORC) proteins establish the pre-replicative complex (preRC) at the origins, and this is essential for the initiation of DNA replication. Open chromatin structures regulate the efficiency of preRC formation and replication initiation. However, the molecular mechanisms that control chromatin structure, and how the preRC components establish themselves on the chromatin remain to be understood. In human cells, the ORC is a highly dynamic complex with many separate functions attributed to sub-complexes or individual subunits of the ORC, including heterochromatin organization, telomere and centromere function, centrosome duplication and cytokinesis. We demonstrate that human Orc5, unlike other ORC subunits, when ectopically tethered to a chromatin locus, induces large-scale chromatin decondensation, predominantly during G1 phase of the cell cycle. Orc5 associates with the H3 histone acetyl transferase GCN5 (also known as KAT2A), and this association enhances the chromatin-opening function of Orc5. In the absence of Orc5, histone H3 acetylation is decreased at the origins. We propose that the ability of Orc5 to induce chromatin unfolding during G1 allows the establishment of the preRC at the origins.