InterPro domain: IPR008721

The Origin Recognition Complex (ORC) is a six-subunit ATP-dependent DNA-binding complex encoded in yeast by ORC1-6 [ 1 ]. ORC is a central component for eukaryotic DNA replication, and binds chromatin at replication origins throughout the cell cycle [ 2 ]. ORC directs DNA replication throughout the genome and is required for its initiation [ 3 , 4 , 5 ]. ORC bound at replication origins serves as the foundation for assembly of the pre-replicative complex (pre-RC), which includes Cdc6, Tah11 (aka Cdt1), and the Mcm2-7 complex [ 6 , 7 , 8 ]. Pre-RC assembly during G1 is required for replication licensing of chromosomes prior to DNA synthesis during S phase [ 9 , 10 , 11 ]. Cell cycle-regulated phosphorylation of ORC2, ORC6, Cdc6, and MCM by the cyclin-dependent protein kinase Cdc28 regulates initiation of DNA replication, including blocking reinitiation in G2/M phase [ 12 , 12 , 13 , 14 ].

In yeast, ORC also plays a role in the establishment of silencing at the mating-type loci Hidden MAT Left (HML) and Hidden MAT Right (HMR) [ 15 , 15 , 15 ]. ORC participates in the assembly of transcriptionally silent chromatin at HML and HMR by recruiting the Sir1 silencing protein to the HML and HMR silencers [ 15 , 15 , 16 ].

Both ORC1 and ORC5 bind ATP, although only ORC1 has ATPase activity [ 17 ]. The binding of ATP by ORC1 is required for ORC binding to DNA and is essential for cell viability [ 18 ]. The ATPase activity of ORC1 is involved in formation of the pre-RC [ 18 , 19 , 20 ]. ATP binding by ORC5 is crucial for the stability of ORC as a whole. Only the ORC1-5 subunits are required for origin binding; ORC6 is essential for maintenance of pre-RCs once formed [ 21 ]. Interactions within ORC suggest that ORC2-3-6 may form a core complex [ 22 ].

ORC homologues have been found in various eukaryotes, including fission yeast, insects, amphibians, and humans [ 22 ].

This entry represents subunit 6, which directs DNA replication by binding to replication origins and is also involved in transcriptional silencing; interacts with Spp1 and with trimethylated histone H3; phosphorylated by Cdc28 [ 23 , 24 ].

In Saccharomyces cerevisiae (Baker's yeast), both ends of the Orc6 interact with Cdt1 [ 25 ] and the N terminus mediates an interaction with the S-phase cyclin Clb5 [ 26 ].

1. Multiple functions of the origin recognition complex. Int. Rev. Cytol. 256, 69-109
2. Yeast two-hybrid analysis of the origin recognition complex of Saccharomyces cerevisiae: interaction between subunits and identification of binding proteins. FEMS Yeast Res. 7, 1263-9
3. ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex. Nature 357, 128-34
4. The multidomain structure of Orc1p reveals similarity to regulators of DNA replication and transcriptional silencing. Cell 83, 563-8
5. Cell cycle execution point analysis of ORC function and characterization of the checkpoint response to ORC inactivation in Saccharomyces cerevisiae. Genes Cells 11, 557-73
6. The origin recognition complex interacts with a bipartite DNA binding site within yeast replicators. Proc. Natl. Acad. Sci. U.S.A. 92, 2224-8
7. Initiation complex assembly at budding yeast replication origins begins with the recognition of a bipartite sequence by limiting amounts of the initiator, ORC. EMBO J. 14, 2631-41
8. ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA. Nat. Struct. Mol. Biol. 12, 965-71
9. Regulation of chromosome replication. Annu. Rev. Biochem. 69, 829-80
10. DNA replication in eukaryotic cells. Annu. Rev. Biochem. 71, 333-74
11. Origin recognition and the chromosome cycle. FEBS Lett. 579, 877-84
12. Binding of cyclin-dependent kinases to ORC and Cdc6p regulates the chromosome replication cycle. Proc. Natl. Acad. Sci. U.S.A. 98, 11211-7
13. Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature 411, 1068-73
14. Disruption of mechanisms that prevent rereplication triggers a DNA damage response. Mol. Cell. Biol. 25, 6707-21
15. Role of interactions between the origin recognition complex and SIR1 in transcriptional silencing. Nature 381, 251-3
16. The origin recognition complex, SIR1, and the S phase requirement for silencing. Science 276, 1547-51
17. Coordinate binding of ATP and origin DNA regulates the ATPase activity of the origin recognition complex. Cell 88, 493-502
18. ATP bound to the origin recognition complex is important for preRC formation. Proc. Natl. Acad. Sci. U.S.A. 98, 8361-7
19. ATP hydrolysis by ORC catalyzes reiterative Mcm2-7 assembly at a defined origin of replication. Mol. Cell 16, 967-78
20. Sequential ATP hydrolysis by Cdc6 and ORC directs loading of the Mcm2-7 helicase. Mol. Cell 21, 29-39
21. An essential role for Orc6 in DNA replication through maintenance of pre-replicative complexes. EMBO J. 25, 5150-8
22. Initiation of DNA replication in eukaryotic cells. Annu. Rev. Cell Dev. Biol. 13, 293-332
23. The origin recognition complex: from simple origins to complex functions. Genes Dev. 16, 659-72
24. Targets of the cyclin-dependent kinase Cdk1. Nature 425, 859-64
25. Orc6 is required for dynamic recruitment of Cdt1 during repeated Mcm2-7 loading. Genes Dev. 21, 2897-907
26. Interaction of the S-phase cyclin Clb5 with an "RXL" docking sequence in the initiator protein Orc6 provides an origin-localized replication control switch. Genes Dev. 18, 981-91