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The Origin Recognition Complex: A Biochemical and Structural View

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The Eukaryotic Replisome: a Guide to Protein Structure and Function

Part of the book series: Subcellular Biochemistry ((SCBI,volume 62))

Abstract

The origin recognition complex (ORC) was first discovered in the baker’s yeast in 1992. Identification of ORC opened up a path for subsequent molecular level investigations on how eukaryotic cells initiate and control genome duplication each cell cycle. Twenty years after the first biochemical isolation, ORC is now taking on a three-dimensional shape, although a very blurry shape at the moment, thanks to the recent electron microscopy and image reconstruction efforts. In this chapter, we outline the current biochemical knowledge about ORC from several eukaryotic systems, with emphasis on the most recent structural and biochemical studies. Despite many species-specific properties, an emerging consensus is that ORC is an ATP-dependent machine that recruits other key proteins to form pre-replicative complexes (pre-RCs) at many origins of DNA replication, enabling the subsequent initiation of DNA replication in S phase.

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References

  • Abdurashidova G, Deganuto M, Klima R, Riva S, Biamonti G, Giacca M, Falaschi A (2000) Start sites of bidirectional DNA synthesis at the human lamin B2 origin. Science 287:2023–2026

    PubMed  CAS  Google Scholar 

  • Abdurashidova G, Danailov MB, Ochem A, Triolo G, Djeliova V, Radulescu S, Vindigni A, Riva S, Falaschi A (2003) Localization of proteins bound to a replication origin of human DNA along the cell cycle. EMBO J 22:4294–4303

    PubMed  CAS  Google Scholar 

  • Aggarwal BD, Calvi BR (2004) Chromatin regulates origin activity in Drosophila follicle cells. Nature 430:372–376

    PubMed  CAS  Google Scholar 

  • Araki M, Wharton RP, Tang Z, Yu H, Asano M (2003) Degradation of origin recognition complex large subunit by the anaphase-promoting complex in Drosophila. EMBO J 22:6115–6126

    PubMed  CAS  Google Scholar 

  • Armache KJ, Garlick JD, Canzio D, Narlikar GJ, Kingston RE (2011) Structural basis of silencing: Sir3 BAH domain in complex with a nucleosome at 3.0 A resolution. Science 334:977–982

    PubMed  CAS  Google Scholar 

  • Asano T, Makise M, Takehara M, Mizushima T (2007) Interaction between ORC and Cdt1p of Saccharomyces cerevisiae. FEMS Yeast Res 7:1256–1262

    PubMed  CAS  Google Scholar 

  • Austin RJ, Orr-Weaver TL, Bell SP (1999) Drosophila ORC specifically binds to ACE3, an origin of DNA replication control element. Genes Dev 13:2639–2649

    PubMed  CAS  Google Scholar 

  • Badugu R, Yoo Y, Singh PB, Kellum R (2005) Mutations in the heterochromatin protein 1 (HP1) hinge domain affect HP1 protein interactions and chromosomal distribution. Chromosoma 113:370–384

    PubMed  CAS  Google Scholar 

  • Baldinger T, Gossen M (2009) Binding of Drosophila ORC proteins to anaphase chromosomes requires cessation of mitotic cyclin-dependent kinase activity. Mol Cell Biol 29:140–149

    PubMed  CAS  Google Scholar 

  • Bartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T (2010) Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell 143:470–484

    PubMed  CAS  Google Scholar 

  • Beall EL, Manak JR, Zhou S, Bell M, Lipsick JS, Botchan MR (2002) Role for a Drosophila Myb-containing protein complex in site-specific DNA replication. Nature 420:833–837

    PubMed  CAS  Google Scholar 

  • Bell SP, Dutta A (2002) DNA replication in eukaryotic cells. Annu Rev Biochem 71:333–374

    PubMed  CAS  Google Scholar 

  • Bell SP, Stillman B (1992) ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex. Nature 357:128–134

    PubMed  CAS  Google Scholar 

  • Bell SP, Kobayashi R, Stillman B (1993) Yeast origin recognition complex functions in transcription silencing and DNA replication. Science 262:1844–1849

    PubMed  CAS  Google Scholar 

  • Bell SP, Mitchell J, Leber J, Kobayashi R, Stillman B (1995) The multidomain structure of Orc1p reveals similarity to regulators of DNA replication and transcriptional silencing. Cell 83:563–568

    PubMed  CAS  Google Scholar 

  • Berquist BR, DasSarma S (2003) An archaeal chromosomal autonomously replicating sequence element from an extreme halophile, Halobacterium sp. strain NRC-1. J Bacteriol 185:5959–5966

    PubMed  CAS  Google Scholar 

  • Bielinsky AK, Gerbi SA (1998) Discrete start sites for DNA synthesis in the yeast ARS1 origin. Science 279:95–98

    PubMed  CAS  Google Scholar 

  • Bielinsky AK, Gerbi SA (2001) Where it all starts: eukaryotic origins of DNA replication. J Cell Sci 114:643–651

    PubMed  CAS  Google Scholar 

  • Bielinsky AK, Blitzblau H, Beall EL, Ezrokhi M, Smith HS, Botchan MR, Gerbi SA (2001) Origin recognition complex binding to a metazoan replication origin. Curr Biol 11:1427–1431

    PubMed  CAS  Google Scholar 

  • Bosco G, Du W, Orr-Weaver TL (2001) DNA replication control through interaction of E2F-RB and the origin recognition complex. Nat Cell Biol 3:289–295

    PubMed  CAS  Google Scholar 

  • Bose ME, McConnell KH, Gardner-Aukema KA, Muller U, Weinreich M, Keck JL, Fox CA (2004) The origin recognition complex and Sir4 protein recruit Sir1p to yeast silent chromatin through independent interactions requiring a common Sir1p domain. Mol Cell Biol 24:774–786

    PubMed  CAS  Google Scholar 

  • Bowers JL, Randell JC, Chen S, Bell SP (2004) ATP hydrolysis by ORC catalyzes reiterative Mcm2-7 assembly at a defined origin of replication. Mol Cell 16:967–978

    PubMed  CAS  Google Scholar 

  • Brewer BJ, Fangman WL (1987) The localization of replication origins on ARS plasmids in S. cerevisiae. Cell 51:463–471

    PubMed  CAS  Google Scholar 

  • Calvi BR, Byrnes BA, Kolpakas AJ (2007) Conservation of epigenetic regulation, ORC binding and developmental timing of DNA replication origins in the genus Drosophila. Genetics 177:1291–1301

    PubMed  CAS  Google Scholar 

  • Cao XQ, Zeng J, Yan H (2008) Structural properties of replication origins in yeast DNA sequences. Phys Biol 5:036012

    PubMed  Google Scholar 

  • Capaldi SA, Berger JM (2004) Biochemical characterization of Cdc6/Orc1 binding to the replication origin of the euryarchaeon Methanothermobacter thermoautotrophicus. Nucleic Acids Res 32:4821–4832

    PubMed  CAS  Google Scholar 

  • Chakraborty A, Shen Z, Prasanth SG (2011) “ORCanization” on heterochromatin: linking DNA replication initiation to chromatin organization. Epigenetics 6:665–670

    PubMed  CAS  Google Scholar 

  • Chang F, May CD, Hoggard T, Miller J, Fox CA, Weinreich M (2011) High-resolution analysis of four efficient yeast replication origins reveals new insights into the ORC and putative MCM binding elements. Nucleic Acids Res 39:6523–6535

    PubMed  CAS  Google Scholar 

  • Chastain PD 2nd, Bowers JL, Lee DG, Bell SP, Griffith JD (2004) Mapping subunit location on the Saccharomyces cerevisiae origin recognition complex free and bound to DNA using a novel nanoscale biopointer. J Biol Chem 279:36354–36362

    PubMed  CAS  Google Scholar 

  • Chaudhuri B, Xu H, Todorov I, Dutta A, Yates JL (2001) Human DNA replication initiation factors, ORC and MCM, associate with oriP of Epstein-Barr virus. Proc Natl Acad Sci USA 98:10085–10089

    PubMed  CAS  Google Scholar 

  • Chen S, Bell SP (2011) CDK prevents Mcm2-7 helicase loading by inhibiting Cdt1 interaction with Orc6. Genes Dev 25:363–372

    PubMed  CAS  Google Scholar 

  • Chen S, de Vries MA, Bell SP (2007) Orc6 is required for dynamic recruitment of Cdt1 during repeated Mcm2-7 loading. Genes Dev 21:2897–2907

    PubMed  CAS  Google Scholar 

  • Chen Z, Speck C, Wendel P, Tang C, Stillman B, Li H (2008) The architecture of the DNA replication origin recognition complex in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 105:10326–10331

    PubMed  CAS  Google Scholar 

  • Chesnokov I, Gossen M, Remus D, Botchan M (1999) Assembly of functionally active Drosophila origin recognition complex from recombinant proteins. Genes Dev 13:1289–1296

    PubMed  CAS  Google Scholar 

  • Chesnokov I, Remus D, Botchan M (2001) Functional analysis of mutant and wild-type Drosophila origin recognition complex. Proc Natl Acad Sci USA 98:11997–12002

    PubMed  CAS  Google Scholar 

  • Chesnokov IN, Chesnokova ON, Botchan M (2003) A cytokinetic function of Drosophila ORC6 protein resides in a domain distinct from its replication activity. Proc Natl Acad Sci USA 100:9150–9155

    PubMed  CAS  Google Scholar 

  • Chuang RY, Kelly TJ (1999) The fission yeast homologue of Orc4p binds to replication origin DNA via multiple AT-hooks. Proc Natl Acad Sci USA 96:2656–2661

    PubMed  CAS  Google Scholar 

  • Chuang RY, Chretien L, Dai J, Kelly TJ (2002) Purification and characterization of the Schizosaccharomyces pombe origin recognition complex: interaction with origin DNA and Cdc18 protein. J Biol Chem 277:16920–16927

    PubMed  CAS  Google Scholar 

  • Clarey MG, Erzberger JP, Grob P, Leschziner AE, Berger JM, Nogales E, Botchan M (2006) Nucleotide-dependent conformational changes in the DnaA-like core of the origin recognition complex. Nat Struct Mol Biol 13:684–690

    PubMed  CAS  Google Scholar 

  • Cocker JH, Piatti S, Santocanale C, Nasmyth K, Diffley JF (1996) An essential role for the Cdc6 protein in forming the pre-replicative complexes of budding yeast. Nature 379:180–182

    PubMed  CAS  Google Scholar 

  • Craig JM, Earle E, Canham P, Wong LH, Anderson M, Choo KH (2003) Analysis of mammalian proteins involved in chromatin modification reveals new metaphase centromeric proteins and distinct chromosomal distribution patterns. Hum Mol Genet 12:3109–3121

    PubMed  CAS  Google Scholar 

  • Cvetic C, Walter JC (2005) Eukaryotic origins of DNA replication: could you please be more specific? Semin Cell Dev Biol 16:343–353

    PubMed  CAS  Google Scholar 

  • DePamphilis ML (2003) The ‘ORC cycle’: a novel pathway for regulating eukaryotic DNA replication. Gene 310:1–15

    PubMed  CAS  Google Scholar 

  • DePamphilis ML (2005) Cell cycle dependent regulation of the origin recognition complex. Cell Cycle 4:70–79

    PubMed  CAS  Google Scholar 

  • DePamphilis ML, Blow JJ, Ghosh S, Saha T, Noguchi K, Vassilev A (2006) Regulating the licensing of DNA replication origins in metazoa. Curr Opin Cell Biol 18:231–239

    PubMed  CAS  Google Scholar 

  • Deshpande AM, Newlon CS (1992) The ARS consensus sequence is required for chromosomal origin function in Saccharomyces cerevisiae. Mol Cell Biol 12:4305–4313

    PubMed  CAS  Google Scholar 

  • Dhar SK, Dutta A (2000) Identification and characterization of the human ORC6 homolog. J Biol Chem 275:34983–34988

    PubMed  CAS  Google Scholar 

  • Dhar SK, Delmolino L, Dutta A (2001a) Architecture of the human origin recognition complex. J Biol Chem 276:29067–29071

    PubMed  CAS  Google Scholar 

  • Dhar SK, Yoshida K, Machida Y, Khaira P, Chaudhuri B, Wohlschlegel JA, Leffak M, Yates J, Dutta A (2001b) Replication from oriP of Epstein-Barr virus requires human ORC and is inhibited by geminin. Cell 106:287–296

    PubMed  CAS  Google Scholar 

  • Diffley JF, Labib K (2002) The chromosome replication cycle. J Cell Sci 115:869–872

    PubMed  CAS  Google Scholar 

  • Drury LS, Perkins G, Diffley JF (1997) The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast. EMBO J 16:5966–5976

    PubMed  CAS  Google Scholar 

  • Drury LS, Perkins G, Diffley JF (2000) The cyclin-dependent kinase Cdc28p regulates distinct modes of Cdc6p proteolysis during the budding yeast cell cycle. Curr Biol 10:231–240

    PubMed  CAS  Google Scholar 

  • Dueber EL, Corn JE, Bell SD, Berger JM (2007) Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex. Science 317:1210–1213

    PubMed  CAS  Google Scholar 

  • Dueber EC, Costa A, Corn JE, Bell SD, Berger JM (2011) Molecular determinants of origin discrimination by Orc1 initiators in archaea. Nucleic Acids Res 39:3621–3631

    PubMed  CAS  Google Scholar 

  • Duncker BP, Pasero P, Braguglia D, Heun P, Weinreich M, Gasser SM (1999) Cyclin B-cdk1 kinase stimulates ORC- and Cdc6-independent steps of semiconservative plasmid replication in yeast nuclear extracts. Mol Cell Biol 19:1226–1241

    PubMed  CAS  Google Scholar 

  • Duncker BP, Chesnokov IN, McConkey BJ (2009) The origin recognition complex protein family. Genome Biol 10:214

    PubMed  Google Scholar 

  • Eaton ML, Galani K, Kang S, Bell SP, MacAlpine DM (2010) Conserved nucleosome positioning defines replication origins. Genes Dev 24:748–753

    PubMed  CAS  Google Scholar 

  • Eaton ML, Prinz JA, MacAlpine HK, Tretyakov G, Kharchenko PV, MacAlpine DM (2011) Chromatin signatures of the Drosophila replication program. Genome Res 21:164–174

    PubMed  CAS  Google Scholar 

  • Ehrentraut S, Hassler M, Oppikofer M, Kueng S, Weber JM, Mueller JW, Gasser SM, Ladurner AG, Ehrenhofer-Murray AE (2011) Structural basis for the role of the Sir3 AAA + domain in silencing: interaction with Sir4 and unmethylated histone H3K79. Genes Dev 25:1835–1846

    PubMed  CAS  Google Scholar 

  • Evrin C, Clarke P, Zech J, Lurz R, Sun J, Uhle S, Li H, Stillman B, Speck C (2009) A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication. Proc Natl Acad Sci USA 106:20240–20245

    PubMed  CAS  Google Scholar 

  • Falaschi A, Abdurashidova G, Sandoval O, Radulescu S, Biamonti G, Riva S (2007) Molecular and structural transactions at human DNA replication origins. Cell Cycle 6:1705–1712

    PubMed  CAS  Google Scholar 

  • Fox CA, Ehrenhofer-Murray AE, Loo S, Rine J (1997) The origin recognition complex, SIR1, and the S phase requirement for silencing. Science 276:1547–1551

    PubMed  CAS  Google Scholar 

  • Gaczynska M, Osmulski PA, Jiang Y, Lee JK, Bermudez V, Hurwitz J (2004) Atomic force microscopic analysis of the binding of the Schizosaccharomyces pombe origin recognition complex and the spOrc4 protein with origin DNA. Proc Natl Acad Sci USA 101:17952–17957

    PubMed  CAS  Google Scholar 

  • Gardner KA, Rine J, Fox CA (1999) A region of the Sir1 protein dedicated to recognition of a silencer and required for interaction with the Orc1 protein in Saccharomyces cerevisiae. Genetics 151:31–44

    PubMed  CAS  Google Scholar 

  • Gaudier M, Schuwirth BS, Westcott SL, Wigley DB (2007) Structural basis of DNA replication origin recognition by an ORC protein. Science 317:1213–1216

    PubMed  CAS  Google Scholar 

  • Gavin KA, Hidaka M, Stillman B (1995) Conserved initiator proteins in eukaryotes. Science 270:1667–1671

    PubMed  CAS  Google Scholar 

  • Georlette D, Ahn S, MacAlpine DM, Cheung E, Lewis PW, Beall EL, Bell SP, Speed T, Manak JR, Botchan MR (2007) Genomic profiling and expression studies reveal both positive and negative activities for the Drosophila Myb MuvB/dREAM complex in proliferating cells. Genes Dev 21:2880–2896

    PubMed  CAS  Google Scholar 

  • Ghosh S, Vassilev AP, Zhang J, Zhao Y, DePamphilis ML (2011) Assembly of the human origin recognition complex occurs through independent nuclear localization of its components. J Biol Chem 286:23831–23841

    PubMed  CAS  Google Scholar 

  • Gibson DG, Bell SP, Aparicio OM (2006) Cell cycle execution point analysis of ORC function and characterization of the checkpoint response to ORC inactivation in Saccharomyces cerevisiae. Genes Cells 11:557–573

    PubMed  CAS  Google Scholar 

  • Gilbert DM (1998) Replication origins in yeast versus metazoa: separation of the haves and the have nots. Curr Opin Genet Dev 8:194–199

    PubMed  CAS  Google Scholar 

  • Gilbert DM (2010) Evaluating genome-scale approaches to eukaryotic DNA replication. Nat Rev Genet 11:673–684

    PubMed  CAS  Google Scholar 

  • Giordano-Coltart J, Ying CY, Gautier J, Hurwitz J (2005) Studies of the properties of human origin recognition complex and its Walker A motif mutants. Proc Natl Acad Sci USA 102:69–74

    PubMed  CAS  Google Scholar 

  • Gossen M, Pak DT, Hansen SK, Acharya JK, Botchan MR (1995) A Drosophila homolog of the yeast origin recognition complex. Science 270:1674–1677

    PubMed  CAS  Google Scholar 

  • Grainge I, Scaife S, Wigley DB (2003) Biochemical analysis of components of the pre-replication complex of Archaeoglobus fulgidus. Nucleic Acids Res 31:4888–4898

    PubMed  CAS  Google Scholar 

  • Harland RM, Laskey RA (1980) Regulated replication of DNA microinjected into eggs of Xenopus laevis. Cell 21:761–771

    PubMed  CAS  Google Scholar 

  • Hartl T, Boswell C, Orr-Weaver TL, Bosco G (2007) Developmentally regulated histone modifications in Drosophila follicle cells: initiation of gene amplification is associated with histone H3 and H4 hyperacetylation and H1 phosphorylation. Chromosoma 116:197–214

    PubMed  CAS  Google Scholar 

  • Hemerly AS, Prasanth SG, Siddiqui K, Stillman B (2009) Orc1 controls centriole and centrosome copy number in human cells. Science 323:789–793

    PubMed  CAS  Google Scholar 

  • Hickman MA, Rusche LN (2010) Transcriptional silencing functions of the yeast protein Orc1/Sir3 subfunctionalized after gene duplication. Proc Natl Acad Sci USA 107:19384–19389

    PubMed  CAS  Google Scholar 

  • Hou Z, Bernstein DA, Fox CA, Keck JL (2005) Structural basis of the Sir1-origin recognition complex interaction in transcriptional silencing. Proc Natl Acad Sci USA 102:8489–8494

    PubMed  CAS  Google Scholar 

  • Houchens CR, Lu W, Chuang RY, Frattini MG, Fuller A, Simancek P, Kelly TJ (2008) Multiple mechanisms contribute to Schizosaccharomyces pombe origin recognition complex-DNA interactions. J Biol Chem 283:30216–30224

    PubMed  CAS  Google Scholar 

  • Huang RY, Kowalski D (1993) A DNA unwinding element and an ARS consensus comprise a replication origin within a yeast chromosome. EMBO J 12:4521–4531

    PubMed  CAS  Google Scholar 

  • Huang DW, Fanti L, Pak DT, Botchan MR, Pimpinelli S, Kellum R (1998) Distinct cytoplasmic and nuclear fractions of Drosophila heterochromatin protein 1: their phosphorylation levels and associations with origin recognition complex proteins. J Cell Biol 142:307–318

    PubMed  CAS  Google Scholar 

  • Huijbregts RP, Svitin A, Stinnett MW, Renfrow MB, Chesnokov I (2009) Drosophila Orc6 facilitates GTPase activity and filament formation of the septin complex. Mol Biol Cell 20:270–281

    PubMed  CAS  Google Scholar 

  • Julien MD, Polonskaya Z, Hearing J (2004) Protein and sequence requirements for the recruitment of the human origin recognition complex to the latent cycle origin of DNA replication of Epstein-Barr virus oriP. Virology 326:317–328

    PubMed  CAS  Google Scholar 

  • Karnani N, Taylor CM, Malhotra A, Dutta A (2010) Genomic study of replication initiation in human chromosomes reveals the influence of transcription regulation and chromatin structure on origin selection. Mol Biol Cell 21:393–404

    PubMed  CAS  Google Scholar 

  • Kawakami H, Katayama T (2010) DnaA, ORC, and Cdc6: similarity beyond the domains of life and diversity. Biochem Cell Biol 88:49–62

    PubMed  CAS  Google Scholar 

  • Kearsey SE, Montgomery S, Labib K, Lindner K (2000) Chromatin binding of the fission yeast replication factor Mcm4 occurs during anaphase and requires ORC and cdc18. EMBO J 19:1681–1690

    PubMed  CAS  Google Scholar 

  • Kelly TJ, Martin GS, Forsburg SL, Stephen RJ, Russo A, Nurse P (1993) The fission yeast cdc18 + gene product couples S phase to START and mitosis. Cell 74:371–382

    PubMed  CAS  Google Scholar 

  • Kim JC, Orr-Weaver TL (2011) Analysis of a Drosophila amplicon in follicle cells highlights the diversity of metazoan replication origins. Proc Natl Acad Sci USA 108:16681–16686

    PubMed  CAS  Google Scholar 

  • Kim JC, Nordman J, Xie F, Kashevsky H, Eng T, Li S, MacAlpine DM, Orr-Weaver TL (2011) Integrative analysis of gene amplification in Drosophila follicle cells: parameters of origin activation and repression. Genes Dev 25:1384–1398

    PubMed  CAS  Google Scholar 

  • Klemm RD, Bell SP (2001) ATP bound to the origin recognition complex is important for preRC formation. Proc Natl Acad Sci USA 98:8361–8367

    PubMed  CAS  Google Scholar 

  • Klemm RD, Austin RJ, Bell SP (1997) Coordinate binding of ATP and origin DNA regulates the ATPase activity of the origin recognition complex. Cell 88:493–502

    PubMed  CAS  Google Scholar 

  • Kong D, DePamphilis ML (2002) Site-specific ORC binding, pre-replication complex assembly and DNA synthesis at Schizosaccharomyces pombe replication origins. EMBO J 21:5567–5576

    PubMed  CAS  Google Scholar 

  • Kreitz S, Ritzi M, Baack M, Knippers R (2001) The human origin recognition complex protein 1 dissociates from chromatin during S phase in HeLa cells. J Biol Chem 276:6337–6342

    PubMed  CAS  Google Scholar 

  • Ladenburger EM, Keller C, Knippers R (2002) Identification of a binding region for human origin recognition complex proteins 1 and 2 that coincides with an origin of DNA replication. Mol Cell Biol 22:1036–1048

    PubMed  CAS  Google Scholar 

  • Lee DG, Bell SP (1997) Architecture of the yeast origin recognition complex bound to origins of DNA replication. Mol Cell Biol 17:7159–7168

    PubMed  CAS  Google Scholar 

  • Lee DG, Bell SP (2000) ATPase switches controlling DNA replication initiation. Curr Opin Cell Biol 12:280–285

    PubMed  CAS  Google Scholar 

  • Lee DG, Makhov AM, Klemm RD, Griffith JD, Bell SP (2000) Regulation of origin recognition complex conformation and ATPase activity: differential effects of single-stranded and double-stranded DNA binding. EMBO J 19:4774–4782

    PubMed  CAS  Google Scholar 

  • Lee JK, Moon KY, Jiang Y, Hurwitz J (2001) 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 98:13589–13594

    PubMed  CAS  Google Scholar 

  • Liang C, Weinreich M, Stillman B (1995) ORC and Cdc6p interact and determine the frequency of initiation of DNA replication in the genome. Cell 81:667–676

    PubMed  CAS  Google Scholar 

  • Lidonnici MR, Rossi R, Paixao S, Mendoza-Maldonado R, Paolinelli R, Arcangeli C, Giacca M, Biamonti G, Montecucco A (2004) Subnuclear distribution of the largest subunit of the human origin recognition complex during the cell cycle. J Cell Sci 117:5221–5231

    PubMed  CAS  Google Scholar 

  • Lipford JR, Bell SP (2001) Nucleosomes positioned by ORC facilitate the initiation of DNA replication. Mol Cell 7:21–30

    PubMed  CAS  Google Scholar 

  • Liu S, Balasov M, Wang H, Wu L, Chesnokov IN, Liu Y (2011) Structural analysis of human Orc6 protein reveals a homology with transcription factor TFIIB. Proc Natl Acad Sci USA 108:7373–7378

    PubMed  CAS  Google Scholar 

  • Liu J, McConnell K, Dixon M, Calvi BR (2012) Analysis of model replication origins in Drosophila reveals new aspects of the chromatin landscape and its relationship to origin activity and the prereplicative complex. Mol Biol Cell 23:200–212

    PubMed  CAS  Google Scholar 

  • Loupart ML, Krause SA, Heck MS (2000) Aberrant replication timing induces defective chromosome condensation in Drosophila ORC2 mutants. Curr Biol 10:1547–1556

    PubMed  CAS  Google Scholar 

  • MacAlpine DM, Rodriguez HK, Bell SP (2004) Coordination of replication and transcription along a Drosophila chromosome. Genes Dev 18:3094–3105

    PubMed  CAS  Google Scholar 

  • MacAlpine HK, Gordan R, Powell SK, Hartemink AJ, MacAlpine DM (2010) Drosophila ORC localizes to open chromatin and marks sites of cohesin complex loading. Genome Res 20:201–211

    PubMed  CAS  Google Scholar 

  • Makise M, Takehara M, Kuniyasu A, Matsui N, Nakayama H, Mizushima T (2009) Linkage between phosphorylation of the origin recognition complex and its ATP binding activity in Saccharomyces cerevisiae. J Biol Chem 284:3396–3407

    PubMed  CAS  Google Scholar 

  • Marahrens Y, Stillman B (1992) A yeast chromosomal origin of DNA replication defined by multiple functional elements. Science 255:817–823

    PubMed  CAS  Google Scholar 

  • Matsuda K, Makise M, Sueyasu Y, Takehara M, Asano T, Mizushima T (2007) Yeast two-hybrid analysis of the origin recognition complex of Saccharomyces cerevisiae: interaction between subunits and identification of binding proteins. FEMS Yeast Res 7:1263–1269

    PubMed  CAS  Google Scholar 

  • Mendez J, Stillman B (2003) Perpetuating the double helix: molecular machines at eukaryotic DNA replication origins. Bioessays 25:1158–1167

    PubMed  CAS  Google Scholar 

  • Mendez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B (2002) Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Mol Cell 9:481–491

    PubMed  CAS  Google Scholar 

  • Moon KY, Kong D, Lee JK, Raychaudhuri S, Hurwitz J (1999) Identification and reconstitution of the origin recognition complex from Schizosaccharomyces pombe. Proc Natl Acad Sci USA 96:12367–12372

    PubMed  CAS  Google Scholar 

  • Muller P, Park S, Shor E, Huebert DJ, Warren CL, Ansari AZ, Weinreich M, Eaton ML, MacAlpine DM, Fox CA (2010) The conserved bromo-adjacent homology domain of yeast Orc1 functions in the selection of DNA replication origins within chromatin. Genes Dev 24:1418–1433

    PubMed  CAS  Google Scholar 

  • Natale DA, Umek RM, Kowalski D (1993) Ease of DNA unwinding is a conserved property of yeast replication origins. Nucleic Acids Res 21:555–560

    PubMed  CAS  Google Scholar 

  • Nguyen VQ, Co C, Li JJ (2001) Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature 411:1068–1073

    PubMed  CAS  Google Scholar 

  • Nishitani H, Nurse P (1997) The cdc18 protein initiates DNA replication in fission yeast. Prog Cell Cycle Res 3:135–142

    PubMed  CAS  Google Scholar 

  • Noguchi K, Vassilev A, Ghosh S, Yates JL, DePamphilis ML (2006) The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo. EMBO J 25:5372–5382

    PubMed  CAS  Google Scholar 

  • Norseen J, Thomae A, Sridharan V, Aiyar A, Schepers A, Lieberman PM (2008) RNA-dependent recruitment of the origin recognition complex. EMBO J 27:3024–3035

    PubMed  CAS  Google Scholar 

  • Ogawa Y, Takahashi T, Masukata H (1999) Association of fission yeast Orp1 and Mcm6 proteins with chromosomal replication origins. Mol Cell Biol 19:7228–7236

    PubMed  CAS  Google Scholar 

  • Ozaydin B, Rine J (2010) Expanded roles of the origin recognition complex in the architecture and function of silenced chromatin in Saccharomyces cerevisiae. Mol Cell Biol 30:626–639

    PubMed  CAS  Google Scholar 

  • Pak DT, Pflumm M, Chesnokov I, Huang DW, Kellum R, Marr J, Romanowski P, Botchan MR (1997) Association of the origin recognition complex with heterochromatin and HP1 in higher eukaryotes. Cell 91:311–323

    PubMed  CAS  Google Scholar 

  • Perkins G, Drury LS, Diffley JF (2001) Separate SCF(CDC4) recognition elements target Cdc6 for proteolysis in S phase and mitosis. EMBO J 20:4836–4845

    PubMed  CAS  Google Scholar 

  • Pflumm MF, Botchan MR (2001) Orc mutants arrest in metaphase with abnormally condensed chromosomes. Development 128:1697–1707

    PubMed  CAS  Google Scholar 

  • Piatti S, Bohm T, Cocker JH, Diffley JF, Nasmyth K (1996) Activation of S-phase-promoting CDKs in late G1 defines a “point of no return” after which Cdc6 synthesis cannot promote DNA replication in yeast. Genes Dev 10:1516–1531

    PubMed  CAS  Google Scholar 

  • Pillus L, Rine J (1989) Epigenetic inheritance of transcriptional states in S. cerevisiae. Cell 59:637–647

    PubMed  CAS  Google Scholar 

  • Pillus L, Rine J (2004) SIR1 and the origin of epigenetic states in Saccharomyces cerevisiae. Cold Spring Harb Symp Quant Biol 69:259–265

    PubMed  CAS  Google Scholar 

  • Prasanth SG, Prasanth KV, Stillman B (2002) Orc6 involved in DNA replication, chromosome segregation, and cytokinesis. Science 297:1026–1031

    PubMed  CAS  Google Scholar 

  • Prasanth SG, Prasanth KV, Siddiqui K, Spector DL, Stillman B (2004) Human Orc2 localizes to centrosomes, centromeres and heterochromatin during chromosome inheritance. EMBO J 23:2651–2663

    PubMed  CAS  Google Scholar 

  • Prasanth SG, Shen Z, Prasanth KV, Stillman B (2010) Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization. Proc Natl Acad Sci USA 107:15093–15098

    PubMed  CAS  Google Scholar 

  • Randell JC, Bowers JL, Rodriguez HK, Bell SP (2006) Sequential ATP hydrolysis by Cdc6 and ORC directs loading of the Mcm2-7 helicase. Mol Cell 21:29–39

    PubMed  CAS  Google Scholar 

  • Ranjan A, Gossen M (2006) A structural role for ATP in the formation and stability of the human origin recognition complex. Proc Natl Acad Sci USA 103:4864–4869

    PubMed  CAS  Google Scholar 

  • Rao H, Stillman B (1995) The origin recognition complex interacts with a bipartite DNA binding site within yeast replicators. Proc Natl Acad Sci USA 92:2224–2228

    PubMed  CAS  Google Scholar 

  • Rao H, Marahrens Y, Stillman B (1994) Functional conservation of multiple elements in yeast chromosomal replicators. Mol Cell Biol 14:7643–7651

    PubMed  CAS  Google Scholar 

  • Remus D, Beall EL, Botchan MR (2004) DNA topology, not DNA sequence, is a critical determinant for Drosophila ORC-DNA binding. EMBO J 23:897–907

    PubMed  CAS  Google Scholar 

  • Remus D, Blanchette M, Rio DC, Botchan MR (2005) CDK phosphorylation inhibits the DNA-binding and ATP-hydrolysis activities of the Drosophila origin recognition complex. J Biol Chem 280:39740–39751

    PubMed  CAS  Google Scholar 

  • Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JF (2009) Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing. Cell 139:719–730

    PubMed  CAS  Google Scholar 

  • Romero J, Lee H (2008) Asymmetric bidirectional replication at the human DBF4 origin. Nat Struct Mol Biol 15:722–729

    PubMed  CAS  Google Scholar 

  • Rowley A, Cocker JH, Harwood J, Diffley JF (1995) 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 14:2631–2641

    PubMed  CAS  Google Scholar 

  • Royzman I, Austin RJ, Bosco G, Bell SP, Orr-Weaver TL (1999) ORC localization in Drosophila follicle cells and the effects of mutations in dE2F and dDP. Genes Dev 13:827–840

    PubMed  CAS  Google Scholar 

  • Ryba T, Hiratani I, Lu J, Itoh M, Kulik M, Zhang J, Schulz TC, Robins AJ, Dalton S, Gilbert DM (2010) Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res 20:761–770

    PubMed  CAS  Google Scholar 

  • Santocanale C, Diffley JF (1996) ORC- and Cdc6-dependent complexes at active and inactive chromosomal replication origins in Saccharomyces cerevisiae. EMBO J 15:6671–6679

    PubMed  CAS  Google Scholar 

  • Sasaki T, Gilbert DM (2007) The many faces of the origin recognition complex. Curr Opin Cell Biol 19:337–343

    PubMed  CAS  Google Scholar 

  • Scholefield G, Veening JW, Murray H (2011) DnaA and ORC: more than DNA replication initiators. Trends Cell Biol 21:188–194

    PubMed  CAS  Google Scholar 

  • Shareef MM, King C, Damaj M, Badagu R, Huang DW, Kellum R (2001) Drosophila heterochromatin protein 1 (HP1)/origin recognition complex (ORC) protein is associated with HP1 and ORC and functions in heterochromatin-induced silencing. Mol Biol Cell 12:1671–1685

    PubMed  CAS  Google Scholar 

  • Shareef MM, Badugu R, Kellum R (2003) HP1/ORC complex and heterochromatin assembly. Genetica 117:127–134

    PubMed  CAS  Google Scholar 

  • Shen Z, Sathyan KM, Geng Y, Zheng R, Chakraborty A, Freeman B, Wang F, Prasanth KV, Prasanth SG (2010) A WD-repeat protein stabilizes ORC binding to chromatin. Mol Cell 40:99–111

    PubMed  CAS  Google Scholar 

  • Sher N, Bell GW, Li S, Nordman J, Eng T, Eaton ML, Macalpine DM, Orr-Weaver TL (2012) Developmental control of gene copy number by repression of replication initiation and fork progression. Genome Res 22:64–75

    PubMed  CAS  Google Scholar 

  • Siddiqui K, Stillman B (2007) ATP-dependent assembly of the human origin recognition complex. J Biol Chem 282:32370–32383

    PubMed  CAS  Google Scholar 

  • Speck C, Stillman B (2007) Cdc6 ATPase activity regulates ORC x Cdc6 stability and the selection of specific DNA sequences as origins of DNA replication. J Biol Chem 282:11705–11714

    PubMed  CAS  Google Scholar 

  • Speck C, Chen Z, Li H, Stillman B (2005) ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA. Nat Struct Mol Biol 12:965–971

    PubMed  CAS  Google Scholar 

  • Spradling AC (1999) ORC binding, gene amplification, and the nature of metazoan replication origins. Genes Dev 13:2619–2623

    PubMed  CAS  Google Scholar 

  • Stefanovic D, Stanojcic S, Vindigni A, Ochem A, Falaschi A (2003) In vitro protein-DNA interactions at the human lamin B2 replication origin. J Biol Chem 278:42737–42743

    PubMed  CAS  Google Scholar 

  • Sun J, Kawakami H, Zech J, Speck C, Stillman B, Li H (2012) Cdc6-induced conformational changes in ORC bound to origin DNA revealed by cryo-electron microscopy. Structure 20:534–544

    PubMed  CAS  Google Scholar 

  • Tada S, Kundu LR, Enomoto T (2008) Insight into initiator-DNA interactions: a lesson from the archaeal ORC. Bioessays 30:208–211

    PubMed  CAS  Google Scholar 

  • Takahashi T, Ohara E, Nishitani H, Masukata H (2003) Multiple ORC-binding sites are required for efficient MCM loading and origin firing in fission yeast. EMBO J 22:964–974

    PubMed  CAS  Google Scholar 

  • Takara TJ, Bell SP (2011) Multiple Cdt1 molecules act at each origin to load replication-competent Mcm2-7 helicases. EMBO J 30:4885–4896

    PubMed  CAS  Google Scholar 

  • Takehara M, Makise M, Takenaka H, Asano T, Mizushima T (2008) Analysis of mutant origin recognition complex with reduced ATPase activity in vivo and in vitro. Biochem J 413:535–543

    PubMed  CAS  Google Scholar 

  • Takenaka H, Makise M, Kuwae W, Takahashi N, Tsuchiya T, Mizushima T (2004) ADP-binding to origin recognition complex of Saccharomyces cerevisiae. J Mol Biol 340:29–37

    PubMed  CAS  Google Scholar 

  • Tatsumi Y, Ohta S, Kimura H, Tsurimoto T, Obuse C (2003) The ORC1 cycle in human cells: I. cell cycle-regulated oscillation of human ORC1. J Biol Chem 278:41528–41534

    PubMed  CAS  Google Scholar 

  • Theis JF, Newlon CS (1994) Domain B of ARS307 contains two functional elements and contributes to chromosomal replication origin function. Mol Cell Biol 14:7652–7659

    PubMed  CAS  Google Scholar 

  • Theis JF, Newlon CS (2001) Two compound replication origins in Saccharomyces cerevisiae contain redundant origin recognition complex binding sites. Mol Cell Biol 21:2790–2801

    PubMed  CAS  Google Scholar 

  • Thomae AW, Pich D, Brocher J, Spindler MP, Berens C, Hock R, Hammerschmidt W, Schepers A (2008) Interaction between HMGA1a and the origin recognition complex creates site-specific replication origins. Proc Natl Acad Sci USA 105:1692–1697

    PubMed  CAS  Google Scholar 

  • Triolo T, Sternglanz R (1996) Role of interactions between the origin recognition complex and SIR1 in transcriptional silencing. Nature 381:251–253

    PubMed  CAS  Google Scholar 

  • Tugal T, Zou-Yang XH, Gavin K, Pappin D, Canas B, Kobayashi R, Hunt T, Stillman B (1998) The Orc4p and Orc5p subunits of the Xenopus and human origin recognition complex are related to Orc1p and Cdc6p. J Biol Chem 273:32421–32429

    PubMed  CAS  Google Scholar 

  • Van Houten JV, Newlon CS (1990) Mutational analysis of the consensus sequence of a replication origin from yeast chromosome III. Mol Cell Biol 10:3917–3925

    PubMed  Google Scholar 

  • Vashee S, Simancek P, Challberg MD, Kelly TJ (2001) Assembly of the human origin recognition complex. J Biol Chem 276:26666–26673

    PubMed  CAS  Google Scholar 

  • Vashee S, Cvetic C, Lu W, Simancek P, Kelly TJ, Walter JC (2003) Sequence-independent DNA binding and replication initiation by the human origin recognition complex. Genes Dev 17:1894–1908

    PubMed  CAS  Google Scholar 

  • Vermeulen M, Eberl HC, Matarese F, Marks H, Denissov S, Butter F, Lee KK, Olsen JV, Hyman AA, Stunnenberg HG, Mann M (2010) Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell 142:967–980

    PubMed  CAS  Google Scholar 

  • Wallace JA, Orr-Weaver TL (2005) Replication of heterochromatin: insights into mechanisms of epigenetic inheritance. Chromosoma 114:389–402

    PubMed  CAS  Google Scholar 

  • Weber JM, Irlbacher H, Ehrenhofer-Murray AE (2008) Control of replication initiation by the Sum1/Rfm1/Hst1 histone deacetylase. BMC Mol Biol 9:100

    PubMed  Google Scholar 

  • Weinreich M, Liang C, Chen HH, Stillman B (2001) Binding of cyclin-dependent kinases to ORC and Cdc6p regulates the chromosome replication cycle. Proc Natl Acad Sci USA 98:11211–11217

    PubMed  CAS  Google Scholar 

  • Wigley DB (2009) ORC proteins: marking the start. Curr Opin Struct Biol 19:72–78

    PubMed  CAS  Google Scholar 

  • Wilmes GM, Bell SP (2002) The B2 element of the Saccharomyces cerevisiae ARS1 origin of replication requires specific sequences to facilitate pre-RC formation. Proc Natl Acad Sci USA 99:101–106

    PubMed  CAS  Google Scholar 

  • Wilmes GM, Archambault V, Austin RJ, Jacobson MD, Bell SP, Cross FR (2004) 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 18:981–991

    PubMed  CAS  Google Scholar 

  • Wu PY, Nurse P (2009) Establishing the program of origin firing during S phase in fission yeast. Cell 136:852–864

    PubMed  CAS  Google Scholar 

  • Xie F, Orr-Weaver TL (2008) Isolation of a Drosophila amplification origin developmentally activated by transcription. Proc Natl Acad Sci USA 105:9651–9656

    PubMed  CAS  Google Scholar 

  • Zhang Z, Hayashi MK, Merkel O, Stillman B, Xu RM (2002) Structure and function of the BAH-containing domain of Orc1p in epigenetic silencing. EMBO J 21:4600–4611

    PubMed  CAS  Google Scholar 

  • Zou L, Stillman B (2000) Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p-Dbf4p kinase. Mol Cell Biol 20:3086–3096

    PubMed  CAS  Google Scholar 

  • Zou Y, Yu Q, Bi X (2006) Asymmetric positioning of nucleosomes and directional establishment of transcriptionally silent chromatin by Saccharomyces cerevisiae silencers. Mol Cell Biol 26:7806–7819

    PubMed  CAS  Google Scholar 

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Acknowledgements

Research in the authors’ labs is supported by grants from the National Institutes of Health, particularly CA13106 and GM45436.

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Correspondence to Huilin Li .

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Li, H., Stillman, B. (2012). The Origin Recognition Complex: A Biochemical and Structural View. In: MacNeill, S. (eds) The Eukaryotic Replisome: a Guide to Protein Structure and Function. Subcellular Biochemistry, vol 62. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4572-8_3

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