The origin recognition complex in the initiation of DNA replication

Abstract

The origin recognition complex (ORC) is the six-subunit heteromeric protein complex that binds directly to the positions on eukaryotic chromosomes where the protein-DNA complex required for the activation of DNA replication origins assembles. This protein-DNA complex, named the MCM complex, contains the replicative helicases and performs the actual unwinding of the parental DNA duplex (a.k.a. origin activation or firing) at the origin. While there is no evidence that ORC is required for origin unwinding directly, it is nevertheless essential for origin activation because of its key role in the MCM complex loading reaction. ORC loads the MCM complex onto chromosomal DNA during G1-phase, thus “licensing” origins for activation in the subsequent S-phase. To perform this role, ORC directly contacts double-stranded DNA, positioning the substrate onto which the MCM complex must load as well as providing a protein interaction surface to guide MCM complex loading. ORC binds and hydrolyzes ATP, and uses these steps to alter its conformation. These conformational changes in turn alter ORC’s ability to interact with both DNA and partner proteins to achieve a complete MCM complex loading cycle. Other chapters in this volume focus on the steps of the MCM complex loading reaction (a.k.a. pre-RC formation; origin licensing). While a discussion of the ORC’s role in replication initiation naturally requires consideration of this reaction, this chapter emphasizes the current understanding of the structural and functional features of ORC that must impinge on MCM complex loading, and perhaps other as yet undiscovered roles for ORC in DNA replication.