Compact Origins and Where to Find Them: ORC's Guide to Genome-Wide Licensing.

Origin licensing is the first step in the fundamental process of DNA replication, which ensures the accurate transmission of an organism's genetic information. Studies in budding yeast have provided crucial insights into replication origins, revealing sequence-specific features and structural DNA elements guiding helicase loading. Here, we review the recent advances in our understanding of DNA replication origin licensing, focusing on insights into origin architecture and advancements in high-resolution sequencing. Progress in the field demonstrates that origins are compact units that load an individual MCM2-7 double hexamer, which in turn causes steric occlusion of the origin recognition complex (ORC) binding site. We discuss why, in addition to the DNA sequence, DNA shape, DNA flexibility, and correct spacing of A- and B2-elements are crucial for efficient helicase loading. These recent findings provide a mechanistic explanation for the regulation of genome-wide origin licensing and reveal fundamental principles of MCM2-7 helicase loading.