Eukaryotic Replication Origins and Initiation of DNA Replication

Melvin L DePamphilis, National Institutes of Health, Bethesda, Maryland, USA
Mirit I Aladjem, National Cancer Institute, Bethesda, Maryland, USA

Published online: September 2010

DOI: 10.1002/9780470015902.a0001055.pub2

Eukaryotic deoxyribonucleic acid (DNA) replication begins at specific genomic sites called replication origins that serve as assembly sites for prereplication complexes (preRCs). PreRCs include proteins that recognise origin sequences, helicases that separate the two strands of DNA and accessory proteins that facilitate helicase binding and interaction with cell cycle regulatory pathways. Assembly of preRCs is required for initiation of DNA replication which occurs after those complexes recruit additional proteins including DNA polymerases. The sequence requirements for replication origins vary but they all include several distinct DNA elements that act synergistically to facilitate preRC assembly. The number of potential replication origins is higher than the number of actual replication initiation sites. Epigenetic processes and metabolic conditions dynamically select the location of replication initiation events of each cell cycle to insure complete and accurate replication of the entire genome in coordination with gene expression and chromatin condensation.

Key Concepts:

  • Replication initiates at distinct chromosomal locations that recruit prereplication (preRC) complexes.
  • PreRCs are recruited sequentially, each step subject to strict regulation to prevent rereplication.
  • Cyclin-dependent kinases (CDK) levels change during the cell cycle. Low CDK activity is required for preRC assembly as cells exit mitosis. High CDK activity is required for activation of existing preRCs and initiation of DNA synthesis, while simultaneously suppressing assembly of new preRCs.
  • Replication origin sequences vary among metazoans, but the functions of proteins that bind replication origins are conserved.
  • Eukaryotic origins exhibit a modular structure. Modularity is detectable in single-cell eukaryotes such as yeast and is more pronounced in metazoans, in which replication origins often cluster.
  • Not all potential replication origins are activated in each cell cycle. Utilisation of replication origins is regulated dynamically to facilitate coordination with other metabolic processes occurring on chromatin.
  • Either hyperactivation or suppression of replication origins can damage DNA and cause chromosomal rearrangements, suggesting that spacing replication initiation events at defined intervals facilitates genomic stability.

Keywords: ARS; DNA synthesis; origin recognition proteins; ORC; cell division cycle proteins; Mcm proteins; DNA unwinding; prereplication complex; preinitiation complex; replicator

Figure 1. Basic organisation of replication origins. Red indicates sequence elements that are required under all conditions (core components), whereas yellow indicates sequence elements (transcription factor-binding sites) that facilitate replication under some conditions (auxiliary components). Arrows indicate protein:protein interactions. Origins contain an A:T-rich element (A/T) with adenines on one strand and thymines on the other, an origin recognition element (ORE) and a DNA-unwinding element (DUE).
Figure 2. Assembly and activation of prereplication complexes. Reproduced from Aladjem (2007), with permission from Nature Publishing Group.
Figure 3. Molecular interaction map of the initiation of DNA replication. An interactive version of the map can be found at http://discover.nci.nih.gov/mim. Annotations for the Molecular Interaction Map (an interactive version can be found online: http://discover.nci.nih.gov/mim/).
A1 
ORC, the origin recognition complex, is a complex of six subunits. ORC binds chromosomal sites that are capable of initiating DNA replication. In yeast cells, ORC recognises autonomous replicating sequences (ARS elements; Bell and Stillman, 1992) in an adenosine triphosphate (ATP)-dependent manner (Klemm et al., 1997). ORC orthologues were found in other eukaryotes, including mammals (Gavin et al., 1995), but the DNA sequence or structural requirements for mammalian ORC binding had not been elucidated yet. In Drosophila, ORC binds the chorion gene replication origin, ACE3 (Austin et al., 1999).
A2 
ORC1 associates less tightly than other subunits in the formation of the ORC complex (Saha et al., 1998). In Xenopus, it may leave the complex during S phase (Rowles et al., 1996; Natale et al., 2000); similar observations suggest that this also happens in mammals (Kreitz et al., 2001; Méndez and Stillman, 2000).
A3 
ORC1 is phosphorylated by Cyclin A and Cyclin B complexes (Ohtani et al., 1996; Wolf et al., 1996). ORC1 is ubiquitinated and released from chromatin during S phase (Li and DePamphilis, 2002).
A4 
ORC2–4 form a tight complex (Ishiai et al., 1997; Quintana et al., 1997). ORC2 and 3 may form a tighter complex that binds ORC4 (Vashee et al., 2001). The ORC2–4 complex localises to chromatin depending on E2F (E2 transcription factor) in Drosophila (Austin et al., 1999). The ORC2–4 complex is hyperphosphorylated on ORC2 at M phase (Carpenter et al., 1996; Carpenter and Dunphy, 1998).
A5 
ORC5 forms a complex with ORC2–4 (Ishiai et al., 1997; Quintana et al., 1997; Vashee et al., 2001). ORC5 directly interacts with CDC6 in yeast (Liang et al., 1995).
A6 
ORC6 probably binds only weakly to the other ORC subunits (Vashee et al., 2001). The presence of ORC6 in the prereplication complex (preRC) depends on E2F, as E2F mutants fail to include the ORC6 in the complex (Hateboer et al., 1998).
A7 
Two complexes of ORC subunits can bind DNA:ORC1–6 and ORC2–6. In mammalian cells, ORC1 leaves chromatin after initiation of DNA replication (see interaction 2 for details).
A8 
ORC2 phosphorylation inhibits initiation of DNA replication (Carpenter et al., 1996; Carpenter and Dunphy, 1998).
A9 
CDC6 binds to the ORC:DNA complex at the beginning of G1 and leaves the complex before G1/S (Saha et al., 1998). CDC6 is essential for DNA replication in Xenopus (Williams et al., 1997). In S. pombe, initiation of DNA replication depends on the presence of CDC6 before the end of G1, but not after the activation of CDKs (Coleman et al., 1996). CDC6 interacts directly with ORC (Bell et al., 1993). In Xenopus, it localises near origins (Romanowski et al., 1996).
A10 
CDC6 is phosphorylated primarily by Cyclin A:CDK2 (Brown et al., 1997; Lopez-Girona et al., 1998) and Cyclin E:CDK2 (Jiang et al., 1999). Phosphorylation localises CDC6 to the cytoplasm (Jallepalli et al., 1998; Jiang et al., 1999; Delmolino et al., 2001; Ishimi et al., 1996) and probably targets CDC6 for ubiquitination (Jallepalli and Kelly, 1996). CDC6 binds Cyclin E (Petersen et al., 1999). Phosphorylated CDC6 is transported from the nucleus to the cytoplasm, preventing licensing during S phase (Ishimi et al., 1996).
A11 
CDT1 is part of the preRC. Cdt binding to preRC is essential for loading MCMs to create the preRC (Maiorano et al., 2000).
A12 
CDT1 binding to the ORC complex requires prior binding of CDC6 to the complex (Maiorano et al., 2000).
A13 
Geminin binds CDT1 (Wohlschlegel et al., 2000) and degrades it to prevent loading of MCMs to chromatin (McGarry and Kirschner, 1998).
A14 
The MCM complex, a helicase, is known as a part of the ‘licensing’ complex (Maine et al., 1984). Binding of the MCM complex to the ORC complex on chromatin constitutes the preRC which confers competence for initiation of DNA replication. MCMs associate with origin-specific DNA before initiation of DNA replication; after replication, the association becomes nonspecific (Aparicio et al., 1997; Tanaka et al., 1997). In yeast, MCM–chromatin association depends on CDC6 (Donovan et al., 1997; Ogawa et al., 1999).
A15 
MCM4, 6 and7 are tightly bound to each other (Musahl et al., 1995), loosely bound to the other MCM proteins. This complex exhibits helicase activity (not shown; Ishimi et al., 1996).
A16 
MCM4 is phosphorylated by Cyclin B:CDK1 in Xenopus (Hendrickson et al., 1996) and humans (Todorov et al., 1995; no clear evidence for the kinase identity in human cells, but the same phosphorylation sites as in Xenopus imply that the kinases are the same). Some phosphorylation activity was observed with Cyclin A:CDK1 (Ishimi et al., 2000).
A17 
Phosphorylation of MCM4 reduces the affinity of the MCM complex to chromatin and reduces the helicase activity of the MCM complex (Hendrickson et al., 1996).
A18 
MCM3 forms a tight complex with MCM5 (Kimura et al., 1995; Schulte et al., 1996). MCM3/MCM5 forms a looser complex with the other MCM proteins (Sherman et al., 1998).
A19 
MCM2 loosely associated with the MCM4, 6 and 7, complex (Sherman et al., 1998).
A20 
MCM2 is a target of phosphorylation by a kinase family that includes Cdc7 in yeast and hsk1 (homolog of cdc seven kinase 1) in humans (Jiang et al., 1999; Masai et al., 2000; Lei et al., 1997; Oshiro et al., 1999; Weinreich et al., 1999). Phosphorylation facilitates binding of MCM2 to other MCM subunits (see interaction 21).
A21 
MCM2 phosphorylation by Cdc7 type kinases (Cdc7:DBF4 in yeast, hsk/dpf4 in humans) facilitates binding of MCM2 to other MCM subunits and initiation of DNA replication (Masai et al., 2000).
A22 
MCM10 associates with DNA polymerase alpha. MCM10:DNA polymerase alpha associate with MCM2–7 and chromatin in humans (Izumi et al., 2000). MCM10 is required for assembly of the preRC in S. cerevisiae (Homesley et al., 2000), Xenopus (Walter, 2000; Jares and Blow, 2000) and human cells. Binding of MCM10 to chromatin seems to occur throughout the cell cycle (Izumi et al., 2001; Lee et al., 2003).
A23 
Cdc45 incorporates into the preRC (Zou and Stillman, 1998) and is essential for initiation of DNA replication in yeast. Cdc45 co-immunoprecipitates with MCMs (Hopwood and Dalton, 1996). In yeast, Cdc45 interacts with MCMs (Hennessy et al., 1991) and ORC2 (Aparicio et al., 1997; Zou and Stillman, 1998), and its association with DNA depends on CDC6 and MCM (Zou and Stillman, 1998; Aparicio et al., 1997). Cdc45 binding to chromatin, but not Cdc45 transcription, requires an active E2F in Drosophila (Arata et al., 2000). Chromatin binding is inhibited by the DNA damage checkpoint (Costanzo et al., 2000).
A24 
Binding of Cdc45 to the ORC:MCM complex on chromatin necessitates two kinase complexes: S phase Cyclin:CDK, especially Cyclin E:CDK2, and homologs of yeast Cdc7:DBF4 (DDK-hsk1 in humans). The yeast homologue of Cyclin E:CDK2 was shown to be required for Cdc45 binding to chromatin in yeast (Zou and Stillman, 1998); Cdc7:DBF4 was shown to be also necessary (Nougarède et al., 2000; Zou and Stillman, 2000). Cdc7:DBF4 was shown directly to phosphorylate Cdc45.
A25 
Double-stranded breaks inhibit the addition of Cdc45 to the preinitiation complex (ORC:MCM:Cdc7) in Xenopus extracts. This inhibition depends on the activity of the ataxia telangiectasia mutated (ATM) kinase (Costanzo et al., 2000). ATM-dependent activation of MreI:nbs:Rad50 complex can also inhibit progression through S phase, but this activation does not inhibit binding of Cdc45 to chromatin (Falck et al., 2002).
A26 
Cdc45 immunoprecipitates with origin DNA before initiation, but binds nonspecifically to DNA after initiation of DNA replication (Aparicio et al., 1997). Cdc45 interacts with DNA polymerase alpha (Mimura and Takisawa, 1998) and HsCdc45 associates with ORC2 (Saha et al., 1998).
A27 
MCM10, possibly in complex with DNA polymerase alpha, binds to the chromatin-bound MCM complex and this binding is essential for recruitment of Cdc45 to the preinitiation complex (Lee et al., 2003).
A28 
Cyclin-dependent kinases can phosphorylate various components of the licensing and initiation pathways as a complex with their appropriate cyclin partners. Cyclins are synthesised at specific times during the cell cycle and regulate kinase activities. These interactions are inhibited by phosphorylation of the kinases which can be relieved by phosphatases of the Cdc25 family (see interaction 43) or by small molecule inhibitors such as p21 (see interactions 29, 30 and 33).
A29 
CDK2 can bind either Cyclin A or Cyclin E. For details on activation of CDK2, see Kohn (1999).
A30 
Cdc2 (CDK1), in association with either Cyclin B or Cyclin A, phosphorylates ORC2. Phosphorylation inhibits initiation of DNA replication. Cyclin B:Cdc2 phosphorylates ORC in vitro, and probably prevents replication during mitosis (Kelly and Brown, 2000). In S. pombe, ORC2 is phosphorylated by Cdc2 (Lygerou and Nurse, 1999) and phosphorylation helps prevent reinitiation (Vas et al., 2001). Cyclin A:Cdc2 binds ORC and phosphorylates ORC2p in Xenopus (Romanowski et al., 2000).
A31 
Cyclin B:CDK1 complexes are mitotic complexes. These kinase complexes phosphorylate MCM4, an inhibitory phosphorylation which reduces binding of the MCM complex to chromatin (Hendrickson et al., 1996).
A32 
Cyclin B1:CDK1 phosphorylates ORC1 and ORC2 during mitosis (Ohtani et al., 1996; Wolf et al., 1996; Kelly and Brown, 2000).
A33 
The transcription factor p53 facilitates the synthesis of various molecules involved in cellular response to genotoxic conditions. Among others, it facilitates transcription of the cyclin-dependent kinase inhibitor p21, gadd45 and molecules involved in apoptosis. For details, see Kohn (1999).
A34 
During interphase, the activity of the Cyclin B:CDK1 complex is inhibited by the phosphorylation of CDK1 on Thr 14 and Thr 15 by Wee1 (Parker and Piwnica-Worms, 1992).
A35 
CDK2, in combination with its cyclin partners, phosphorylates Cdc45 and facilitates its binding to licensed DNA in concert with another phosphorylation mediated by hsk1/dpf4 (Nougarède et al., 2000).
A36 
CDK2, in combination with its cyclin partners, phosphorylates CDC6 and targets it for transport to the cytoplasm and degradation (Brown et al., 1997; Lopez-Girona et al., 1998; Jiang et al., 1999; Ishimi et al., 1996).
A37 
Cyclin A:CDK2 phosphorylates ORC1 (Findeisen et al., 1999).
A38 
Inhibition of DNA replication by the DNA topoisomerase I inhibitor camptothecin, or by UV irradiation activates the ATR (ataxia telangiectasia-Rad3-related)-dependent pathway of the S phase checkpoint (Guo et al., 2000). The first step in the pathway is the binding of ATR to its partner ATRIP (ATR interacting protein)
A39 
Checkpoint kinase 2 (CHK2) is phosphorylated after replication arrest by ATR, the homologue of yeast Rad3/Mec1 (Boddy et al., 1998; Sun et al., 1996; Lindsay et al., 1998). Rad3/Mec2 is required for in vitro phosphorylation of cds1 (Martinho et al., 1998). In yeast, cds1 is involved in the mitosis checkpoint: regulates phosphorylation of CDKs, Cyclin B:CDK1 through Wee and Mik (Enoch and Nurse, 1990; Rhind and Russell, 1998; Lundgren et al., 1991).
A40 
Phosphorylation of Wee1 by CHK1 on Ser549 enhances its ability to bind 14-3-3 proteins during interphase (not shown) and increases kinase activity of Wee1 (Lee et al., 2001). Kinase activity during interphase guards against premature activation of the mitotic Cyclin:CDK complexes (e.g. Cyclin B:CDK1) and prevents mitotic entry as a part of the G2/M checkpoint. For more details on Wee1 interactions see Kohn (1999).
A41 
CHK1 phosphorylates Cdc25A in response to DNA damage (Furnari et al., 1999; Peng et al., 1997).
A42 
Phosphorylation of Cdc25A leads to its exclusion from the nucleus in yeast (Zeng et al., 1998; Peng et al., 1997). The phosphorylated protein cannot activate the mitotic Cyclin B:CDK1 complex (Lopez-Girona et al., 1999; Zeng and Piwnica-Worms, 1999).
A43 
Cdc25A phosphatase activity is required for activation of CDKs (Hoffmann et al. (1994); Jinno et al., 1994). CHK2-mediated phosphorylation following irradiation and activation by ATM leads to degradation of Cdc25A (Falck et al., 2001).
A44 
Double-stranded DNA breaks trigger the signal transduction cascade, whose first step is phosphorylation by the ATM kinase. These phosphorylation steps lead to inhibition of further initiation of DNA replication on licensed DNA by inhibiting the hsk1/dpf4 and the cyclin-dependent kinases (see interactions 47–49), and may trigger apoptosis through the p53-mediated pathway (see interaction 50). There is also some evidence that ATM may directly inhibit binding of Cdc45 to licensed chromatin (see interaction 45).
A45 
ATM may directly inhibit binding of Cdc45 to licensed chromatin through a pathway that does not involve the inhibitor Cdc25A to disallow cyclin-dependent kinase activity (Falck et al., 2001).
A46 
ATM phosphorylates p53 in response to DNA damage (Banin et al., 1998; Tibbetts et al., 1999). This phosphorylation may lead to p53-mediated apoptosis. For details see Kohn (1999).
A47 
HsCds1/CHK2 is phosphorylated after irradiation, and formation of DNA strand breaks, but not after treatment with the drug hydroxyurea (Matsuoka et al., 1998; Brown et al., 1999).
A48 
CHK2 phosphorylates Cdc25A after DNA damage (Furnari et al., 1999; Ford et al., 1994; Peng et al., 1997).
A49 
Hsk1/dpf4 is the human orthologue of yeast Cdc7:DBF4. Cdc7:DBF4 is required for the onset of replication in yeast and prevention of reassembly of preRC on origins (Bousset and Diffley, 1998; Schwob et al., 1994; Dahmann et al., 1995; Piatti et al., 1996). DBF4 is the regulatory protein; its expression levels regulate Cdc7 activity (Brown et al., 1999). The DBF4 mouse homologue interacts with MCM2 (Lepke et al., 1999).
A50 
Hsk1:dfp1 phosphorylates MCM2 (Lei et al., 1997) and Cdc45 (Zou and Stillman, 1998).
A51 
Binding of MCM10 to dfp1 facilitates kinase activity of hsk1 (Lee et al., 2003).
A52 
Activation of the S phase checkpoint in Xenopus inhibits hsk1:dfp1 kinase activity through a mechanism which requires ATR ( Costanzo et al., 2003).
A53 
Auto-phosphorylation of hsk1 inhibits the activity of the hsk1:dfp1 complex (Izumi et al., 2001).
A54 
MCM10 is phosphorylated in G2/M, and this phosphorylation leads to its degradation (Izumi et al., 2001).
A55 
DNA damage or potential genotoxic conditions trigger the signal transduction cascade mediated by the transcription factor p53. For details, see reference Kohn (1999).
A56 
SLD3 is recruited to licensed replication origins, interacting with the MCM complex (Kanemaki and Labib, 2006; Yabuuchi et al., 2006).
A57 
SLD3 loading on chromatin requires Cdc7-DBF4 (Yabuuchi et al., 2006).
A58 
SLD3 recruits GINS complex to licensed origins (Kanemaki and Labib, 2006; Yabuuchi et al., 2006).
A59 
SLD3 interacts with Cdc45; both proteins associate with early origins during G1 and with late origins during late S phase in yeast (Kamimura et al., 2001).
A60 
CDKs phosphorylate SLD3 (Zegerman and Diffley, 2007).
A61 
CDKs phosphorylate SLD2 (Zegerman and Diffley, 2007).
A62 
Phosphorylation of SLD2 and SLD3 is required for initiation of DNA replication (Liu et al., 2004; Zegerman and Diffley, 2007).
A63 
SLD3 loading on chromatin is required for GINS loading (Takayama et al., 2003).
A64 
After phosphorylatoin by CDKs, SLD3 binds DPB11 (orthologue of TOPBP1) in yeast; Liu et al., 2004; Zegerman and Diffley, 2007); similar results were obtained in Xenopus (Hashimoto and Takisawa, 2003).
A65 
SLD2 interacts with DPB11 in yeast (Kamimura et al., 1998).
A66 
Phosphorylation of SLD2 by CDKs is essential for initiation (Masumoto et al., 2002).
A67 
Association of TOPBP1 and phosphorylation of SLD2 and SLD3 by CDKs are essential for recruitment of Cdc45 to chromatin (the cited works only mention TOPBP1 recruitement and CDK activity and do not specify the SLDs; Hashimoto and Takisawa, 2003).
A68 
MCM10 recruits polymerase alpha to chromatin for initiation (Ricke and Bielinsky, 2004; Zhu et al., 2007) and is involved in regulation of replication elongation as well as initiation (Chattopadhyay and Bielinsky, 2007).
A69 
MCM10 association with chromatin is required for the phosphorylation of MCMs by Cdc7 (Lee et al., 2003).
A70 
MCM10 chromatin association stimulates binding of Cdc45 (Wohlschlegel et al., 2002).
A71 
GINS maintains association of Cdc45 with MCMs during elongation (Gambus et al., 2006).
A72 
TOPBP1 is involved in recruitment of Cdc45 to chromatin (Schmidt et al., 2008).
A73 
Polo-like kinase is required for Cdc45 loading on chromatin (Trenz et al., 2008).
A74 
GINS loading on chromatin, presumably via the MCM complex, is essential for loading Cdc45 (Takayama et al., 2003).
A75 
GINS interaction with Cdc45 is required for Cdc45 loading on chromatin (Yabuuchi et al., 2006).
Figure 4. Replication origins that function in eukaryotic cells. The Simian virus 40 (SV40) core origin (64 bp) consists of an origin recognition element (ORE) that is required for T-antigen binding, an easily unwound sequence (DNA-unwinding element, DUE) where DNA unwinding begins and an A:T-rich element containing adenines on one strand and thymines on the other. Together these components occupy ~160 bp of DNA and exhibit autonomously replicating sequence (ARS) activity. Auxiliary elements bind a T-antigen dimer (aux-1) and transcription factor Sp1 (aux-2). The spacing and orientation of these elements are critical and therefore represent a rigid modular anatomy. Replication origins in the budding yeast Saccharomyces cerevisiae consist of 100–150 bp that exhibit ARS activity. Origins consist of two core elements (A and B1) that occupy ~43 bp and constitute the binding site for the six-protein origin recognition complex (ORC), and a DUE that generally contains a genetically defined B2 element. Some origins also contain an auxiliary element (B3) that binds transcription factor Abf-1. Each element is interchangeable with homologous elements from other S. cerevisiae origins and therefore exhibits a flexible modular anatomy. Yeast origins are context sensitive. Replication origins in the fission yeast S. pombe consist of at least one ARS element that is 0.5–1 kb in size. In some cases, multiple ARS elements in close proximity form an initiation zone in which replication bubbles appear to occur randomly, but in fact, originate from specific ARS elements. Whether or not S. pombe origins exhibit a modular anatomy is not yet known. In mammalian cells, some origins consist of a large intergenic initiation zone (shaded region) defined by two-dimensional gel origin-mapping methods and one or more high-frequency initiation sites (OBRs) defined by nascent strand origin-mapping methods (e.g. the dhfr and rrna gene regions). Other origins such as the Lamin B2 gene region consist of a single OBR that exhibits a cell cycle-dependent DNA footprint (ORC?) reminiscent of those at S. cerevisiae origins. The Lamin B2 origin also overlaps three transcription factor-binding sites belonging to the promoter of a downstream gene. Initiation events in the intergenic region (0.6 kb) downstream of the Lamin B gene have not been analysed by two-dimensional gel analysis.
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 Further Reading
    Antequera F (2004) Genomic specification and epigenetic regulation of eukaryotic DNA replication origins. The EMBO Journal 23: 4365–4370.
    Blow JJ and Gillespie PJ (2008) Replication licensing and cancer – a fatal entanglement? Nature Reviews. Cancer 8: 799–806.
    Donaldson AD (2005) Shaping time: chromatin structure and the DNA replication programme. Trends in Genetics 21: 444–449.
    Machida YJ, Hamlin JL and Dutta A (2005) Right place, right time, and only once: replication initiation in metazoans. Cell 123: 13–24.
    Sclafani RA and Holzen TM (2007) Cell cycle regulation of DNA replication. Annual Review of Genetics 41: 237–280.

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Article Title: Eukaryotic Replication Origins and Initiation of DNA Replication
 
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DePamphilis, Melvin L, and Aladjem, Mirit I(Sep 2010) Eukaryotic Replication Origins and Initiation of DNA Replication. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001055.pub2]