Intrinsically disordered regions navigate DNA replication licensing factors to specific genomic loci.

Sites of DNA replication initiation are determined by binding of the Origin Recognition Complex (ORC, composed of Orc1-6) to specific genomic loci. Here, we determine the mechanism underlying site-specific binding of human Orc1. We find that Orc1's Bromo-Adjacent Homology (BAH) domain functions as an avidity element, whereas an intrinsically disordered region (IDR) guides genomic specificity. Deletion of the IDR abolishes chromatin binding and Orc1 chimeras with swapped IDRs are redirected to new genomic locations. Other replication factors, such as Cdt1 and Cdc6, also possess IDRs. However, despite their similar biochemical properties, we find that these IDRs are functionally non-equivalent. Like Orc1, the Cdt1 IDR guides loci-specific binding but targets distinct sites. Strikingly, the Cdt1 IDR, when swapped into Orc1, redirects Orc1 to Cdt1 binding sites. This establishes a key role for the Orc1 IDR in genome navigation and points to impressive levels of functional sophistication in licensing factor disordered regions.