- Protein family review
- Open Access
The origin recognition complex protein family
© BioMed Central Ltd 2009
- Published: 17 March 2009
Origin recognition complex (ORC) proteins were first discovered as a six-subunit assemblage in budding yeast that promotes the initiation of DNA replication. Orc1-5 appear to be present in all eukaryotes, and include both AAA+ and winged-helix motifs. A sixth protein, Orc6, shows no structural similarity to the other ORC proteins, and is poorly conserved between budding yeast and most other eukaryotic species. The replication factor Cdc6 has extensive sequence similarity with Orc1 and phylogenetic analysis suggests the genes that encode them may be paralogs. ORC proteins have also been found in the archaea, and the bacterial DnaA replication protein has ORC-like functional domains. In budding yeast, Orc1-6 are bound to origins of DNA replication throughout the cell cycle. Following association with Cdc6 in G1 phase, the sequential hydrolysis of Cdc6 - then ORC-bound ATP loads the Mcm2-7 helicase complex onto DNA. Localization of ORC subunits to the kinetochore and centrosome during mitosis and to the cleavage furrow during cytokinesis has been observed in metazoan cells and, along with phenotypes observed following knockdown with short interfering RNAs, point to additional roles at these cell-cycle stages. In addition, ORC proteins function in epigenetic gene silencing through interactions with heterochromatin factors such as Sir1 in budding yeast and HP1 in higher eukaryotes. Current avenues of research have identified roles for ORC proteins in the development of neuronal and muscle tissue, and are probing their relationship to genome integrity.
- Replication Factor
- Origin Recognition Complex
- Cleavage Furrow
- Metazoan Cell
- Septin Ring
ORC-like proteins are not just confined to the eukaryotes. Genes with homology to ORC1 and CDC6 have been found in most species of archaea, which typically have 1 to 9 copies, although as many as 17 have been found in the case of Haloarcula marismortui (reviewed in ). Studies of archaeal ORC proteins have yielded important results, because they not only bind to defined origin sequences but are amenable to crystallization, which has provided important structural information about ORC-DNA interactions [14, 15]. Curiously, genome analysis of several Methanococcus species has uncovered no evidence of ORC-like sequences. Given the apparent functional conservation of ORC proteins between eukaryotes and archaea, it will be interesting to determine whether ORC orthologs have simply been overlooked as a result of lower sequence conservation, or whether these species have developed another means of initiating DNA replication at origin sequences.
Evidence that proteins with ORC-like functions are actually common to all domains of life is provided by investigations of the bacterial DnaA protein. DnaA, like ORC, acts as an initiator of DNA replication and, whereas DnaA and the archaeal Orc1/Cdc6 proteins share little sequence identity, structural studies have shown that they do have a high degree of similarity in some of their functional domains . Moreover, a recent study of Drosophila ORC structure suggests that DnaA and ORC wrap DNA in a similar manner .
Orc1-5 as well as Cdc6 have conserved AAA+ folds, including Walker A and Walker B ATP-binding domains, characteristic of ATP-dependent clamp-loading proteins, which allow ring-shaped protein complexes to encircle duplex DNA (see Figure 1). Sensor-1 and Sensor-2 motifs are also found within the AAA+ fold and are believed to detect whether ADP or ATP is bound and to contribute to ATPase activity . These domains are located centrally, in the case of Orc1 and Orc2, and towards the amino termini in Cdc6, Orc3, Orc4, and Orc5. Near the carboxyl termini of these proteins a winged-helix domain is present that mediates DNA binding [14, 15, 17]. Somewhat surprisingly, structural studies of archaeal Orc1 suggest that the AAA+ domain also contributes to its association with origin sequences [14, 15]. Interestingly, Cdc6 has been shown to act like an additional ORC subunit, associating with the complex in the G1 phase of the cell cycle and inducing a conformational change that increases its sequence specificity for DNA binding [19, 20]. When Cdc6 is bound to ORC, a ring-like structure is predicted with structural similarities to the Mcm2-7 helicase complex that ORC-Cdc6 loads onto DNA in an ATP-dependent manner [19, 21].
As mentioned above, sequence similarity has been identified for Orc1 and Sir3, with a particularly high degree of conservation between their amino-terminal 214 amino acids (50% identical, 63% similar), which includes a BAH (bromo-adjacent homology) protein-protein interaction domain [6, 22]. Sir3 is required for transcriptional silencing of telomeres and mating-type loci, functions that are also ORC-dependent [3, 5, 23], as discussed below. Although formally a member of ORC, Orc6 contains none of the aforementioned structural features, and shows no evidence of a common evolutionary origin with Orc1-5. It is nevertheless considered an ORC protein as its association with the other five subunits is required to promote the initiation of DNA replication. Relative to other ORC subunits, Orc6 is poorly conserved between budding yeast and metazoan eukaryotes  (see Figure 2). Nevertheless, a number of important domains specific to Orc6 have been identified in S. cerevisiae, including an amino-terminal 'RXL' docking sequence (amino acids 177-183) which mediates an interaction with the S-phase cyclin Clb5 , and a carboxy-terminal region (the last 62 amino acids) which associates with the other ORC subunits. Both ends of Orc6 (amino-terminal 185 amino acids, carboxy-terminal 165 amino acids) interact with Cdt1, another replication factor required to load Mcm2-7 onto DNA . In both human and Drosophila cells, Orc6 plays a role in cytokinesis, and studies with the latter organism have identified a carboxy-terminal domain that interacts with the septin Pnut, a component of the septin ring that forms in cell division, as well as an amino-terminal domain that is important for DNA binding [26–29]. Interestingly, structural modeling of Drosophila Orc6 revealed that the amino terminus, but not the carboxyl terminus, is homologous to the human transcription factor TFIIB, raising the possibility that proteins involved in replication and transcription may have coevolved .
Detection of ORC by immunofluorescence and live-cell imaging of fluorescently tagged subunits in budding yeast have demonstrated that it localizes to punctate subnuclear foci throughout the cell cycle [30, 31]. Moreover, chromatin immunoprecipitation (ChIP) of ORC-bound genomic DNA that was subsequently labeled and hybridized to high-density, tiled, whole-genome S. cerevisiae oligonucleotide arrays revealed 400 ORC-enriched regions, which included 70 of the 96 replication origins that had been experimentally verified previously . These findings are consistent with a role for ORC as a scaffold for the sequential association of a number of additional replication factors in G1 phase of the cell cycle, including Cdc6, Cdt1, and Mcm2-7, which collectively form the pre-replicative complex (pre-RC), required for the initiation of DNA (reviewed in ).
Binding sites for budding yeast ORC have been identified at HML (hidden MAT left), and HMR (hidden MAT right) silent cassettes, used for mating-type switching through gene conversion of the MAT allele, and at telomeric loci, whereas the majority of Drosophila ORC appears to be associated with heterochromatin, consistent with the role of this complex in mediating gene silencing [23, 33]. The amino terminus of S. cerevisiae Orc1 interacts with the hetero-chromatin factor Sir1, and truncation mutants lacking this region are defective in silencing but not DNA replication [6, 34], indicating that these two functions of the protein are separable. The role of the Orc1 amino terminus in mediating transcriptional repression seems to be conserved among eukaryotes, as it has also been found to interact with hetero-chromatin protein 1 (HP1) in Xenopus and Drosophila  which, in a fashion similar to Sir1, helps to propagate silenced chromatin.
It appears that all six ORC subunits remain chromatin-associated throughout the cell cycle in S. cerevisiae , but this differs from observations in metazoan cells where, in a number of cases, Orc1 appears to be absent from ORC at certain points in the cell cycle. For example, in human HeLa cells, Orc1 dissociates from chromatin during S phase, and then reassociates at the end of mitosis (reviewed in ). Immunofluorescent detection of Orc2 in one study indicated that it is found on chromatin throughout the cell cycle in Drosophila embryos ; however, a similar analysis with Drosophila neuroblasts and recently reported live-cell imaging of Orc2-green fluorescent protein (GFP) in embryos argue that this protein is actually excluded from chromosomes from prophase until anaphase [37, 38]. Fluorescence loss in photobleaching analysis in hamster cells suggests that the interaction of ORC subunits with chromatin may be less static than previously thought, revealing a highly dynamic interaction for both Orc1 and Orc4 with chromatin throughout the cell cycle .
In metazoan cells, ORC localization clearly extends beyond origin sequences (reviewed in ). Studies with Drosophila and human cells have revealed that Orc6 also localizes to the cleavage furrow in dividing cells, and a role for this protein in cytokinesis has been confirmed in both organisms through depletion by RNA interference [26, 27]. In addition, human Orc6 was shown to localize to kinetochores and reticular-like structures around the cell periphery during mitosis, and it is required for the proper progression of this cell-cycle stage , whereas human Orc2 also localizes to the centrosome throughout the cell cycle and its depletion results in mitotic defects and multiple centrosomes . Recently, a similar role in controlling centrosome copy number was reported for human Orc1 .
The mechanism by which ORC promotes DNA replication, through loading and maintenance of the Mcm2-7 helicase at origin sequences, has been most closely examined in S. cerevisiae. ATP binding by the Orc1 subunit promotes association with DNA . Cdc6 is then thought to bind ATP and associate with ORC, causing a conformational change that increases the specificity for the conserved origin sequences found in budding yeast. These origin regions are often referred to as autonomously replicating sequences (ARSs), and include an 11-bp ARS consensus sequence (ACS), as well as one or more B elements [20, 21, 23]. Cross-linking analysis has shown interactions between Orc1, Orc2, Orc4, and Orc5 proteins and origin DNA .
Given the lack of such conserved origin sequences in other eukaryotes, it is not surprising that other means by which ORC association with DNA is promoted have been discovered. Some of these are related to the relatively high AT content that is a common feature of replication origins among diverse species. For example, in the fission yeast S. pombe, a domain of Orc4 binds to AT-rich DNA , and another 'AT-hook' protein, HMGA1a, has recently been shown to target ORC to replication origins in human cells . HMGA1a, which is known to interact in a highly specific manner with the minor groove of stretches of AT, was shown to interact with Orc1, Orc2, Orc4 and Orc6. Interestingly, an AT-hook motif is also present in S. cerevisiae Orc2, although its functional significance has not been determined (see Figure 1). It is clear, however, that AT content is not the only origin determinant, as numerous studies with both S. pombe and Drosophila have shown differences in ORC binding between stretches of DNA that have the same proportion of AT . A study of human Orc1 revealed that the BAH domain of this subunit promotes association of ORC with chromatin . Human and Drosophila investigations have pointed to transcription factors, including c-Myc, E2F, and the Myb complex, as likely ORC-targeting factors [48–51], whereas a ribosomal RNA fragment that associates with Tetrahymena ORC has been found to direct the complex to complementary rDNA sequence in the genome of this organism . Furthermore, whereas Orc6 is dispensable for origin binding in S. cerevisiae , it is absolutely required for this function in Drosophila [28, 53].
Rather than merely acting as a landing pad for pre-replicative complex (pre-RC) assembly, S. cerevisiae ORC appears to play an active role in loading additional pre-RC components. Following ORC-Cdc6 binding, Orc6 interacts with Cdt1 to promote Mcm2-7 association with origin DNA [25, 31]. The hydrolysis of Cdc6-bound ATP is then thought to load the initial Mcm2-7 complexes more tightly onto the DNA, and additional Mcm2-7 binding occurs following the hydrolysis of ORC-bound ATP . Interestingly, even though it does not bind ATP itself, a predicted arginine finger in Orc4 is required for Orc1 ATP hydrolysis [54, 55]. Once loaded, the continued presence of Orc6, Cdc6, and most probably other pre-RC components, is required to maintain the Mcm2-7 helicase complex at origins until the initiation of DNA replication [25, 31, 56].
Although it is not known whether the mechanism determined for the promotion of DNA replication by the ORC in budding yeast operates in precisely the same fashion in other organisms, the sequential association of the ORC, Cdc6, Cdt1, and Mcm2-7 at origins appears to be conserved in other eukaryotes, including S. pombe and Xenopus (reviewed in ). Furthermore, several reports have demonstrated interactions between archaeal ORC-Cdc6 and MCM proteins [57–59].
Now that roles for ORC proteins have been established at other points in the cell cycle than simply the G1/S boundary, it is of primary interest to determine the way in which the proper progression of cell-cycle stages might be coordinated by the complex as a whole or by its individual subunits. For example, studies of human Orc6 have shown that it associates with the kinetochore during the G2/prophase transition , and in both human and Drosophila cells it localizes to the cleavage furrow just before cytokinesis [26, 27]. Similarly, a mitotic function has been uncovered for Orc2 in promoting sister-chromatid cohesion in budding yeast after it is no longer required for DNA replication . Thus, it is possible that a redistribution of ORC subunits after their role in DNA replication is complete helps to ensure the proper order of cell-cycle events.
Another avenue of ORC research that is presently yielding intriguing results is the elucidation of roles for these proteins in development . Studies with Drosophila Orc3 have shown that it localizes to larval neuromuscular junctions, and that its mutation leads to impaired neuronal cell proliferation and to learning defects, as judged by a reduction in olfactory memory [63, 64]. Similarly, Orc2-5 have been detected at high levels in mouse brain, and knockdown of Orc3 and Orc5 by short interfering RNAs (siRNAs) impeded dendritic growth . Furthermore, siRNA knockdown of Orc1 was recently shown to inhibit the proliferation of rat smooth muscle cells .
In recent years, numerous ORC-associated proteins have shown promise as biomarkers for early cancer detection (reviewed in ), and alterations in the expression levels of a number of them have been implicated as contributing to human lung carcinomas and mouse mammary adenocarcinomas [68–70]. The extent to which mutations in ORC subunits and/or perturbations of their normal levels may contribute to carcinogenesis is an important unresolved question. Some initial indications have been obtained through the observation that genomic instability, in the form of DNA re-replication, can occur as a result of mutations in combinations of pre-RC components, including Orc2 and Orc6, in budding yeast [71, 72]. Given the finding that ORC plays an active enzymatic role in loading Mcm2-7 onto DNA in S. cerevisiae, it will be very important to determine if the complex acts in the same way in higher eukaryotes, including humans. Interestingly, Drosophila Orc2 interacts with the tumor suppressor protein retinoblastoma 1 (Rb1) and siRNA-mediated reduction in Orc6 levels sensitizes human colon cancer cells to treatment with chemotherapeutic agents, pointing to possible links between ORC subunits and cancer development [73, 74].
Further investigation into both normal and dysregulated ORC function should yield important insights into the way cells coordinate the distinct stages required for their duplication, how they are organized into specific tissue types, and how carcinogenesis occurs.
The writing of this review was supported by funding from the Canadian Institutes of Health Research (BPD), National Institutes of Health Grant GM69681 (INC) and the Natural Sciences and Engineering Research Council of Canada (BJM). BPD is a Research Scientist of the Canadian Cancer Society.
- Bell SP, Stillman B: ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex. Nature. 1992, 357: 128-134. 10.1038/357128a0.PubMedView ArticleGoogle Scholar
- Bell SP, Kobayashi R, Stillman B: Yeast origin recognition complex functions in transcription silencing and DNA replication. Science. 1993, 262: 1844-1849. 10.1126/science.8266072.PubMedView ArticleGoogle Scholar
- Foss M, McNally FJ, Laurenson P, Rine J: Origin recognition complex (ORC) in transcriptional silencing and DNA replication in S. cere-visiae. Science. 1993, 262: 1838-1844. 10.1126/science.8266071.PubMedView ArticleGoogle Scholar
- Li JJ, Herskowitz I: Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system. Science. 1993, 262: 1870-1874. 10.1126/science.8266075.PubMedView ArticleGoogle Scholar
- Micklem G, Rowley A, Harwood J, Nasmyth K, Diffley JF: Yeast origin recognition complex is involved in DNA replication and transcriptional silencing. Nature. 1993, 366: 87-89. 10.1038/366087a0.PubMedView ArticleGoogle Scholar
- Bell SP, Mitchell J, Leber J, Kobayashi R, Stillman B: The multidomain structure of Orc1p reveals similarity to regulators of DNA replication and transcriptional silencing. Cell. 1995, 83: 563-568. 10.1016/0092-8674(95)90096-9.PubMedView ArticleGoogle Scholar
- Loo S, Fox CA, Rine J, Kobayashi R, Stillman B, Bell SP: The origin recognition complex in silencing, cell cycle progression, and DNA replication. Mol Biol Cell. 1995, 6: 741-756.PubMedPubMed CentralView ArticleGoogle Scholar
- Spignola M, Grate L, Haussler D, Ares M: Genome-wide bioinformatic and molecular analysis of introns in Saccharomyces cerevisiae. RNA. 1999, 5: 221-234. 10.1017/S1355838299981682.View ArticleGoogle Scholar
- Gossen M, Pak DT, Hansen SK, Acharya JK, Botchan MR: A Drosophila homolog of the yeast origin recognition complex. Science. 1995, 270: 1674-1677. 10.1126/science.270.5242.1674.PubMedView ArticleGoogle Scholar
- Diaz-Trivino S, del Mar Castellano M, de la Paz Sanchez M, Ramirez-Parra E, Desvoyes B, Gutierrez C: The genes encoding Arabidopsis ORC subunits are E2F targets and the two ORC1 genes are differently expressed in proliferating and endoreplicating cells. Nucleic Acids Res. 2005, 33: 5404-5414. 10.1093/nar/gki854.PubMedPubMed CentralView ArticleGoogle Scholar
- Dhar SK, Dutta A: Identification and characterization of the human ORC6 homolog. J Biol Chem. 2000, 275: 34983-34988. 10.1074/jbc.M006069200.PubMedView ArticleGoogle Scholar
- Giraldo R: Common domains in the initiators of DNA replication in Bacteria, Archaea and Eukarya; combined structural, functional and phylogenetic perspectives. FEMS Microbiol Rev. 2003, 26: 533-554. 10.1111/j.1574-6976.2003.tb00629.x.PubMedView ArticleGoogle Scholar
- Barry ER, Bell SD: DNA replication in the archaea. Microbiol Mol Biol Rev. 2006, 70: 876-887. 10.1128/MMBR.00029-06.PubMedPubMed CentralView ArticleGoogle Scholar
- Dueber EL, Corn JE, Bell SD, Berger JM: Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex. Science. 2007, 317: 1210-1213. 10.1126/science.1143690.PubMedView ArticleGoogle Scholar
- Gaudier M, Schuwirth BS, Westcott SL, Wigley DB: Structural basis of DNA replication origin recognition by an ORC protein. Science. 2007, 317: 1213-1216. 10.1126/science.1143664.PubMedView ArticleGoogle Scholar
- Mott ML, Berger JM: DNA replication initiation: mechanisms and regulation in bacteria. Nat Rev Microbiol. 2007, 5: 343-354. 10.1038/nrmicro1640.PubMedView ArticleGoogle Scholar
- Clarey MG, Botchan M, Nogales E: Single particle EM studies of the Drosophila melanogaster origin recognition complex and evidence for DNA wrapping. J Struct Biol. 2008, 164: 241-249. 10.1016/j.jsb.2008.08.006.PubMedPubMed CentralView ArticleGoogle Scholar
- Iyer LM, Leipe DD, Koonin EV, Aravind L: Evolutionary history and higher order classification of AAA+ ATPases. J Struct Biol. 2004, 146: 11-31. 10.1016/j.jsb.2003.10.010.PubMedView ArticleGoogle Scholar
- Speck C, Chen Z, Li H, Stillman B: ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA. Nat Struct Mol Biol. 2005, 12: 965-971.PubMedPubMed CentralView ArticleGoogle Scholar
- Speck C, Stillman B: Cdc6 ATPase activity regulates ORC-Cdc6 stability and the selection of specific DNA sequences as origins of DNA replication. J Biol Chem. 2007, 282: 11705-11714. 10.1074/jbc.M700399200.PubMedPubMed CentralView ArticleGoogle Scholar
- Randell JCW, Bowers JL, Rodriguez HK, Bell SP: Sequential ATP hydrolysis by Cdc6 and ORC directs loading of the Mcm2-7 helicase. Mol Cell. 2006, 21: 29-39. 10.1016/j.molcel.2005.11.023.PubMedView ArticleGoogle Scholar
- Callebaut I, Courvalin JC, Mornon JP: The BAH (bromo-adjacent homology) domain: a link between DNA methylation, replication and transcriptional regulation. FEBS Lett. 1999, 446: 189-193. 10.1016/S0014-5793(99)00132-5.PubMedView ArticleGoogle Scholar
- Bell SP: The origin recognition complex: from simple origins to complex functions. Genes Dev. 2002, 16: 659-672. 10.1101/gad.969602.PubMedView ArticleGoogle Scholar
- Wilmes GM, Archambault V, Austin RJ, Jacobson MD, Bell SP, Cross FR: Interaction of the S-phase cyclin Clb5 with an 'RXL' docking sequence in the initiator protein Orc6 provides an originlocalized replication control switch. Genes Dev. 2004, 18: 981-991. 10.1101/gad.1202304.PubMedPubMed CentralView ArticleGoogle Scholar
- Chen S, de Vries MA, Bell SP: Orc6 is required for dynamic recruitment of Cdt1 during repeated Mcm2-7 loading. Genes Dev. 2007, 21: 2897-2907. 10.1101/gad.1596807.PubMedPubMed CentralView ArticleGoogle Scholar
- Prasanth SG, Prasanth KV, Stillman B: Orc6 involved in DNA replication, chromosome segregation and cytokinesis. Science. 2002, 297: 1026-1031. 10.1126/science.1072802.PubMedView ArticleGoogle Scholar
- Chesnokov IN, Chesnokova ON, Botchan M: A cytokinetic function of Drosophila ORC6 protein resides in a domain distinct from its replication activity. Proc Natl Acad Sci USA. 2003, 100: 9150-9155. 10.1073/pnas.1633580100.PubMedPubMed CentralView ArticleGoogle Scholar
- Balasov M, Huijbregts RPH, Chesnokov I: Role of the Orc6 protein in origin recognition complex-dependent DNA binding and replication in Drosophila melanogaster. Mol Cell Biol. 2007, 27: 3143-3153. 10.1128/MCB.02382-06.PubMedPubMed CentralView ArticleGoogle Scholar
- Huijbregts RPH, Svitin A, Stinnett MW, Renfrow MB, Chesnokov I: Drosophila Orc6 facilitates GTPase activity and filament formation of the septin complex. Mol Biol Cell. 2009, 20: 270-281. 10.1091/mbc.E08-07-0754.PubMedPubMed CentralView ArticleGoogle Scholar
- Pasero P, Duncker BP, Schwob E, Gasser SM: A role for the Cdc7 kinase regulatory subunit Dbf4p in the formation of initiation-competent origins of replication. Genes Dev. 1999, 13: 2159-2176. 10.1101/gad.13.16.2159.PubMedPubMed CentralView ArticleGoogle Scholar
- Semple JW, Da-Silva LF, Jervis EJ, Ah-Kee J, Al-Attar H, Kummer L, Heikkila JJ, Pasero P, Duncker BP: An essential role for Orc6 in DNA replication through maintenance of pre-replicative complexes. EMBO J. 2006, 25: 5150-5158. 10.1038/sj.emboj.7601391.PubMedPubMed CentralView ArticleGoogle Scholar
- Xu W, Aparicio JG, Aparicio OM, Tavare S: Genome-wide mapping of ORC and Mcm2p binding sites on tiling arrays and identification of essential ARS consensus sequences in S. cerevisiae. BMC Genomics. 2006, 7: 276-10.1186/1471-2164-7-276.PubMedPubMed CentralView ArticleGoogle Scholar
- Pak DTS, Pflumm M, Chesnokov I, Huang DW, Kellum R, Marr J, Romanowski P, Botchan MR: Association of the origin recognition complex with heterochromatin and HP1 in higher eukaryotes. Cell. 1997, 91: 311-323. 10.1016/S0092-8674(00)80415-8.PubMedView ArticleGoogle Scholar
- Zhang Z, Hayashi MK, Merkel O, Stillman B, Xu RM: Structure and function of the BAH-containing domain of Orc1p in epigenetic silencing. EMBO J. 2002, 21: 4600-4611. 10.1093/emboj/cdf468.PubMedPubMed CentralView ArticleGoogle Scholar
- Liang C, Stillman B: Persistent initiation of DNA replication and chromatin-bound MCM proteins during the cell cycle in cdc6 mutants. Genes Dev. 1997, 11: 3375-3386. 10.1101/gad.11.24.3375.PubMedPubMed CentralView ArticleGoogle Scholar
- DePamphilis ML: Cell cycle dependent regulation of the origin recognition complex. Cell Cycle. 2005, 4: 70-79.PubMedView ArticleGoogle Scholar
- Loupart M-L, Krause SA, Heck MMS: Aberrant replication timing induces defective chromosome condensation in Drosophila ORC2 mutants. Curr Biol. 2000, 10: 1547-1556. 10.1016/S0960-9822(00)00844-7.PubMedView ArticleGoogle Scholar
- Baldinger T, Gossen M: Binding of Drosophila Orc proteins to anaphase chromosomes requires cessation of mitotic cyclin-dependent kinase activity. Mol Cell Biol. 2009, 29: 140-149. 10.1128/MCB.00981-08.PubMedPubMed CentralView ArticleGoogle Scholar
- McNairn AJ, Okuno Y, Misteli T, Gilbert DM: Chinese hamster ORC subunits dynamically associate with chromatin throughout the cell-cycle. Exp Cell Res. 2005, 308: 345-356. 10.1016/j.yexcr.2005.05.009.PubMedPubMed CentralView ArticleGoogle Scholar
- Chesnokov I: Multiple functions of the origin recognition complex. Int Rev Cytol. 2007, 256: 69-109. 10.1016/S0074-7696(07)56003-1.PubMedView ArticleGoogle Scholar
- Prasanth SG, Prasanth KV, Siddiqui K, Spector DL, Stillman B: Human Orc2 localizes to centrosomes, centromeres and heterochromatin during chromosome inheritance. EMBO J. 2004, 23: 2651-2663. 10.1038/sj.emboj.7600255.PubMedPubMed CentralView ArticleGoogle Scholar
- Hemerly AS, Prasanth SG, Siddiqui K, Stillman B: Orc1 controls cen-triole and centrosome copy number in human cells. Science. 2009, 323: 789-793. 10.1126/science.1166745.PubMedPubMed CentralView ArticleGoogle Scholar
- Klemm RD, Austin RJ, Bell SP: Coordinate binding of ATP and origin DNA regulates the ATPase activity of the origin recognition complex. Cell. 1997, 88: 493-502. 10.1016/S0092-8674(00)81889-9.PubMedView ArticleGoogle Scholar
- Lee DG, Bell SP: Architecture of the yeast origin recognition complex bound to origins of DNA replication. Mol Cell Biol. 1997, 17: 7159-7168.PubMedPubMed CentralView ArticleGoogle Scholar
- Lee JK, Moon KY, Jiang Y, Hurwitz J: The Schizosaccharomyces pombe origin recognition complex interacts with multiple AT-rich regions of the replication origin DNA by means of the AT-hook domains of the spOrc4 protein. Proc Natl Acad Sci USA. 2001, 98: 13589-13594. 10.1073/pnas.251530398.PubMedPubMed CentralView ArticleGoogle Scholar
- Thomae AW, Pich D, Brocher J, Spindler M-P, Berens C, Hock R, Hammerschmidt W, Schepers A: Interaction between HMG1a and the origin recognition complex creates site-specific replication origins. Proc Natl Acad Sci USA. 2008, 105: 1692-1697. 10.1073/pnas.0707260105.PubMedPubMed CentralView ArticleGoogle Scholar
- Noguchi K, Vassilev A, Ghosh S, Yates JL, Depamphilis ML: The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo. EMBO J. 2006, 25: 5372-5382. 10.1038/sj.emboj.7601396.PubMedPubMed CentralView ArticleGoogle Scholar
- Takayama MA, Taira T, Tamai K, Iguchi-Ariga SM, Ariga H: ORC1 interacts with c-Myc to inhibit E-box-dependent transcription by abrogating c-Myc-SNF5/INI1 interaction. Genes Cells. 2000, 5: 481-490. 10.1046/j.1365-2443.2000.00338.x.PubMedView ArticleGoogle Scholar
- Bosco G, Du W, Orr-Weaver TL: DNA replication control through interaction of E2f-RB and the origin recognition complex. Nat Cell Biol. 2001, 3: 289-295. 10.1038/35060086.PubMedView ArticleGoogle Scholar
- Beall EL, Manak JR, Zhou S, Bell M, Lipsick JS, Botchan MR: Role for a Drosophila Myb-containing protein complex in site-specific DNA replication. Nature. 2002, 420: 833-837. 10.1038/nature01228.PubMedView ArticleGoogle Scholar
- Calvi BR, Byrnes BA, Kolpakas AJ: Conservation of epigenetic regulation, ORC binding and developmental timing of DNA replication origins in the genus Drosophila. Genetics. 2007, 177: 1291-1301. 10.1534/genetics.107.070862.PubMedPubMed CentralView ArticleGoogle Scholar
- Mohammad MM, Donti TR, Yakisich JS, Smith AG, Kapler GM: Tetrahymena ORC contains a ribosomal RNA fragment that participates in rDNA origin recognition. EMBO J. 2007, 26: 5048-5060. 10.1038/sj.emboj.7601919.PubMedPubMed CentralView ArticleGoogle Scholar
- Chesnokov I, Remus D, Botchan M: Functional analysis of mutant and wild-type Drosophila origin recognition complex. Proc Natl Acad Sci USA. 2001, 98: 11997-12002. 10.1073/pnas.211342798.PubMedPubMed CentralView ArticleGoogle Scholar
- Davey MJ, Jeruzalmi D, Kuriyan J, O'Donnell M: Motors and switches: AAA+ machines within the replisome. Nat Rev Mol Cell Biol. 2002, 3: 826-835. 10.1038/nrm949.PubMedView ArticleGoogle Scholar
- Bowers JL, Randell JCW, Chen S, Bell SP: ATP hydrolysis by ORC catalyzes reiterative Mcm2-7 assembly at a defined origin of replication. Mol Cell. 2004, 16: 967-978. 10.1016/j.molcel.2004.11.038.PubMedView ArticleGoogle Scholar
- Aparicio OM, Weinstein DM, Bell SP: Components and dynamics of DNA replication complexes in S. cerevisiae: redistribution of MCM proteins and Cdc45p during S phase. Cell. 2007, 91: 59-69. 10.1016/S0092-8674(01)80009-X.View ArticleGoogle Scholar
- Shin JH, Grabowski B, Kasiviswanathan R, Bell SD, Kelman Z: Regulation of minichromosome maintenance helicase activity by Cdc6. J Biol Chem. 2003, 278: 38059-38067. 10.1074/jbc.M305477200.PubMedView ArticleGoogle Scholar
- Haughland GT, Shin JH, Birkeland NK, Kelman Z: Stimulation of MCM helicase activity by a Cdc6 protein in the archaeon Thermoplasma acidophilum. Nucleic Acids Res. 2006, 34: 6337-6344. 10.1093/nar/gkl864.View ArticleGoogle Scholar
- Atanassova N, Grainge I: Biochemical characterization of the minichromosome maintenance (MCM) protein of the crenarchaeote Aeropyrum pernix and its interactions with the origin recognition complex (ORC) proteins. Biochemistry. 2008, 47: 13362-13370. 10.1021/bi801479s.PubMedView ArticleGoogle Scholar
- Prasanth SG, Méndez J, Prasanth KV, Stillman B: Dynamics of pre-replication complex proteins during the cell division cycle. Phil Trans R Soc Lond B Biol Sci. 2004, 359: 7-16. 10.1098/rstb.2003.1360.View ArticleGoogle Scholar
- Shimada K, Gasser SM: The origin recognition complex functions in sister-chromatid cohesion in Saccharomyces cerevisiae. Cell. 2007, 128: 85-99. 10.1016/j.cell.2006.11.045.PubMedView ArticleGoogle Scholar
- Sasaki T, Gilbert DM: The many faces of the origin recognition complex. Curr Opin Cell Biol. 2007, 19: 337-343. 10.1016/j.ceb.2007.04.007.PubMedView ArticleGoogle Scholar
- Pinto S, Quintana DG, Smith P, Mihalek RM, Hou Z-H, Boynton S, Jones CJ, Hendricks M, Velinzon K, Wohlschlegel JA, Austin RJ, Lane WS, Tully T, Dutta A: latheo encodes a subunit of the origin recognition complex and disrupts neuronal proliferation and adult olfactory memory when mutant. Neuron. 1999, 23: 45-54. 10.1016/S0896-6273(00)80752-7.PubMedView ArticleGoogle Scholar
- Rohrbough J, Pinto S, Mihalek RM, Tully T, Broadie K: latheo, a Drosophila gene involved in learning, regulates functional synaptic plasticity. Neuron. 1999, 23: 55-70. 10.1016/S0896-6273(00)80753-9.PubMedView ArticleGoogle Scholar
- Huang Z, Zang K, Reichardt LF: The origin recognition core complex regulates dendrite and spine development in postmitotic neurons. J Cell Biol. 2005, 170: 527-535. 10.1083/jcb.200505075.PubMedPubMed CentralView ArticleGoogle Scholar
- Shu M, Qin Y, Jiang M: RNA interference targeting ORC1 gene suppresses the proliferation of vascular smooth muscle cells in rats. Exp Mol Pathol. 2008, 84: 206-212. 10.1016/j.yexmp.2008.03.001.PubMedView ArticleGoogle Scholar
- Semple JW, Duncker BP: ORC-associated replication factors as biomarkers for cancer. Biotechnol Adv. 2004, 22: 621-663. 10.1016/j.biotechadv.2004.06.001.PubMedView ArticleGoogle Scholar
- Karakaidos P, Taraviras S, Vassiliou LV, Zacharatos P, Kastrinakis NG, Kougiou D, Kouloukoussa M, Nishitani H, Papavassiliou AG, Lygerou Z, Gorgoulis VG: Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas. Am J Pathol. 2004, 165: 1351-1365.PubMedPubMed CentralView ArticleGoogle Scholar
- Gonzalez S, Klatt P, Delgado S, Conde E, Lopez-Rios F, Sanchez-Cespedes M, Mendez J, Antequera F, Serrano M: Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. Nature. 2006, 440: 702-706. 10.1038/nature04585.PubMedView ArticleGoogle Scholar
- Shima N, Alcaraz A, Liachko I, Buske TR, Andrews CA, Munroe RJ, Hartford SA, Tye BK, Schimenti JC: A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nat Genet. 2007, 39: 93-98. 10.1038/ng1936.PubMedView ArticleGoogle Scholar
- Nguyen VQ, Co C, Li JJ: Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature. 2001, 411: 1068-1073. 10.1038/35082600.PubMedView ArticleGoogle Scholar
- Green BM, Morreale RJ, Ozaydin B, Derisi JL, Li JJ: Genome-wide mapping of DNA synthesis in Saccharomyces cerevisiae reveals that mechanisms preventing reinitiation of DNA are not redundant. Mol Biol Cell. 2006, 17: 2401-2414. 10.1091/mbc.E05-11-1043.PubMedPubMed CentralView ArticleGoogle Scholar
- Ahlander J, Chen X-B, Bosco G: The N-terminal domain of the Drosophila retinoblastoma protein Rbf1 interacts with ORC and associates with chromatin in an E2F independent manner. PLoS ONE. 2008, 3: e2831-10.1371/journal.pone.0002831.PubMedPubMed CentralView ArticleGoogle Scholar
- Gavin EJ, Song B, Wang Y, Xi Y, Ju J: Reduction of Orc6 expression sensitizes human colon cancer cells to 5-fluorouracil and cisplatin. PLoS ONE. 2008, 3: e4054-10.1371/journal.pone.0004054.PubMedPubMed CentralView ArticleGoogle Scholar
- Marchler-Bauer A, Anderson JB, Derbyshire MK, DeWeese-Scott C, Gonzales NR, Gwadz M, Hao L, He S, Hurwitz DI, Jackson JD, Ke Z, Krylov D, Lanczycki CJ, Liebert CA, Liu C, Lu F, Lu S, Marchler GH, Mullokandov M, Song JS, Thanki N, Yamashita RA, Yin JJ, Zhang D, Bryant SH: CDD: a conserved domain database for interactive domain family analysis. Nucleic Acids Res. 2007, 35: D237-D240. 10.1093/nar/gkl951.PubMedPubMed CentralView ArticleGoogle Scholar
- Finn RD, Tate J, Mistry J, Coggill PC, Sammut JS, Hotz HR, Ceric G, Forslund K, Eddy SR, Sonnhammer EL, Bateman A: The Pfam protein families database. Nucleic Acids Res. 2008, 36: D281-D288. 10.1093/nar/gkm960.PubMedPubMed CentralView ArticleGoogle Scholar
- Dosztányi Z, Csizmók V, Tompa P, Simon I: IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics. 2005, 21: 3433-3434. 10.1093/bioinformatics/bti541.PubMedView ArticleGoogle Scholar
- Lupas A, Van Dyke M, Stock J: Predicting coiled coils from protein sequences. Science. 1991, 252: 1162-1164. 10.1126/science.252.5009.1162.PubMedView ArticleGoogle Scholar
- Saha P, Chen J, Thome KC, Lawlis SJ, Hou ZH, Hendricks M, Parvin JD, Dutta A: Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. Mol Cell Biol. 1998, 18: 2758-2767.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang B, Feng L, Hu Y, Huang SH, Reynolds CP, Wu L, Jong AY: The essential role of Saccharomyces cerevisiae CDC6 nucleotide-binding site in cell growth, DNA synthesis, and Orc1 association. J Biol Chem. 1999, 274: 8291-8298. 10.1074/jbc.274.12.8291.PubMedView ArticleGoogle Scholar
- Edgar RC: MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004, 32: 1792-1797. 10.1093/nar/gkh340.PubMedPubMed CentralView ArticleGoogle Scholar
- Gascuel O: BIONJ: an improved version of the NJ algorithm based on a simple model of sequence data. Mol Biol Evol. 1997, 14: 685-695.PubMedView ArticleGoogle Scholar