The regulation of replication origin activation

Current Opinion in Genetics and Development

Volumn 9, Issue 1, 1999, Pages 62-68

  Donaldson, Anne D ^a   Blow, J Julian ^a  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CELL CYCLE S PHASE; CELL DIVISION; CELL PROLIFERATION; DNA REPLICATION ORIGIN; DNA SYNTHESIS; NONHUMAN; PRIORITY JOURNAL; REVIEW;

EID: 0032997834     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(99)80009-4     Document Type: Article

References (68)

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5. Kobayashi T, Rein T, DePamphilis ML Identification of primary initiation sites for DNA replication in the hamster dihydrofolate reductase gene initiation zone. Mol Cell Biol. 18:1998;3266-3277. Replication events in the vicinity of the hamster DHFR origin were mapped by the identification of short nascent strands. This study detected an additional site of preferential initiation, called ori-β′, situated between the previously identified ori-β and ori-γ. This means that the DHFR origin region comprises at least three sites of preferential initiation.
6. Wang S, Dijkwel PA, Hamlin JL Lagging-strand, early-labelling, and two-dimensional gel assays suggest multiple potential initiation sites in the Chinese hamster dihydrofolate reductase origin. Mol Cell Biol. 18:1998;39-50. Replication events in the vicinity of the hamster DHFR origin were mapped by two-dimensional gel electrophoresis, early-labelling fragment hybridisation and by lagging-strand abundance. These methods indicated that initiation events can take place at multiple sites throughout a large 55 kb initiation zone. This initiation zone encompasses ori-β, ori-β′ and ori-γ, sites where the frequency of initiation appears to be higher.
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8. 0 phase. The results are reminiscent of footprints seen at origins in S. cerevisiae. Identification of the causative human proteins would be an exciting advance.
9. 1, after which the DHFR origin is selectively used as an origin in Xenopus egg extracts. Treatment of CHO cells with 2-aminopurine arrests normal cells prior to this ODP. Transformed cells do not arrest in response to 2-aminopurine but instead enter S phase and initiate replication randomly within the DHFR gene rather than at the normal origin. This confirms that the ODP regulates origin selection in mammalian cells and can be bypassed as a consequence of transformation.
10. 2 phase of the cell cycle.
11. Huang DW, Fanti L, Pak DT, Botchan MR, Pimpinelli S, Kellum R Distinct cytoplasmic and nuclear fractions of Drosophila heterochromatin protein 1: their phosphorylation levels and associations with origin recognition complex proteins. J Cell Biol. 142:1998;307-318. Heterochromatin protein 1 (HP1) was here shown to be present in Drosophila embryos in a number of different forms, including a large oligomer that can associate tightly with chromatin. The larger oligomers also form complexes with ORC. This interaction is probably of functional importance as the localisation of HP1 on chromatin in ORC2 mutant embryos is severely disrupted.
12. Pak DT, 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. 91:1997;311-323. Drosophila ORC was found associated with heterochromatin protein 1 (HP1). Both HP1 and Drosophila ORC could be visualised together on interphase and mitotic chromosomes, whereas mutations in both HP1 and ORC affected transcriptional suppression in a similar manner. These results suggest that ORC may play a general role in assembly of different chromatin-associated proteins.
13. Fox CA, Loo S, Dillin A, Rine J The origin recognition complex has essential functions in transcriptional silencing and chromosomal replication. Genes Dev. 9:1995;911-924.
14. 1, by an apparent dominant block to initiation, or in metaphase, by an unknown defect. The mitotic arrest did not appear to be as a result of defective replication, suggesting that Orc5 may be involved in a mitotic function distinct from its role in replication.
15. Lee DG, Bell SP Architecture of the yeast origin recognition complex bound to origins of DNA replication. Mol Cell Biol. 17:1997;7159-7168. Partial ORC complexes lacking any one of the subunits Orc1-5 were unable to efficiently bind ARS DNA; only subcomplexes lacking the smallest subunit, Orc6, were competent for DNA binding. A range of contacts between the ORC subunits and different regions of ARS DNA were observed.
16. Coleman TR, Carpenter PB, Dunphy WG The Xenopus Cdc6 protein is essential for the initiation of a single round of DNA replication in cell-free extracts. Cell. 87:1996;53-63.
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19. 2 phase but is unable to recruit Mcm7, probably because of inhibition by Cdk kinase.
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22. Perkins G, Diffley JF Nucleotide-dependent prereplicative complex assembly by Cdc6p, a homolog of eukaryotic and prokaryotic clamp-loaders. Mol Cell. 2:1998;23-32. A new allele of the CDC6 gene highlights the importance of the putative NTP binding motif. A particular mutation at this site is dominant negative, apparently because it is able to assemble at origins but blocks loading of Mcm/P1 complexes. Sequence similarity with both eukaryotic and prokaryotic clamp-loading proteins supports the idea that Cdc6 belongs to a family of nuceotide-dependent clamp-loading factors.
23. Thömmes P, Kubota Y, Takisawa H, Blow JJ The RLF-M component of the replication licensing system forms complexes containing all six MCM/P1 polypeptides. EMBO J. 16:1997;3312-3319.
24. Sherman DA, Pasion SG, Forsburg SL Multiple domains of fission yeast cdc19p (MCM2) are required for its association with the core MCM complex. Mol Biol Cell. 9:1998;1833-1845. S. pombe Mcm2 (Nda1/Cdc19) was co-immunoprecipitated with a complex of Mcm4 (Cdc12) and Mcm6 (Mis5) proteins. Mutagenesis of the mcm2 gene showed that multiple regions appear to be required for the protein to be assembled into complexes containing other members of the MCM/P1 family.
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26. Kearsey SE, Labib K MCM proteins: evolution, properties, and role in DNA replication. Biochim Biophys Acta. 1398:1998;113-136.
27. 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. 91:1997;59-69. A CHIP assay was used to examine association of ORC, Cdc45, and Mcm4 with S. cerevisiae origins. Mcm4 binding is dependent on Cdc6 and ORC. During S phase, Cdc45 and Mcm4 appear to move with polymerase ε, suggesting that they may be components of the replication fork.
28. Mahbubani HM, Chong JP, Chevalier S, Thommes P, Blow JJ Cell cycle regulation of the replication licensing system: involvement of a Cdk-dependent inhibitor. J Cell Biol. 136:1997;125-135.
29. Ishimi Y A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex. J Biol Chem. 272:1997;24508-24513. A complex containing human Mcm4, Mcm6 and Mcm7 was purified from HeLa cells. This purified complex was associated with a weak helicase activity capable of displacing small (<37 nucleotide) oligomers from DNA, in a 3′ to 5′ direction. These proteins may therefore function as a helicase during DNA replication.
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31. Cip1, or by inhibitors of ubiquitin-mediated proteolysis. Once licensing has occurred, addition of cyclin A to extracts results in the removal of Orc2, but not Mcm3, from the chromatin. The resultant chromatin can replicate in extracts devoid of ORC, suggesting that the essential function of ORC for DNA replication has already been fulfilled at this time.
32. Sato N, Arai K, Masai H Human and Xenopus cDNAs encoding budding yeast Cdc7-related kinases: in vitro phosphorylation of MCM subunits by a putative human homologue of Cdc7. EMBO J. 16:1997;4340-4351. This paper reports the cloning of human and Xenopus homologues of the yeast Cdc7 kinase. The human protein is present in nuclei throughout interphase of the cell cycle.
33. •].
34. •] use different techniques to deplete cells of Cdc7 in late S phase. Under such conditions, late origins fail to fire. Both papers therefore contradict the historical view in showing that Cdc7 is necessary throughout S phase for execution of the normal origin firing programme.
35. Hardy CF, Dryga O, Seematter S, Pahl PM, Sclafani RA mcm5/cdc46-bob1 bypasses the requirement for the S phase activator Cdc7p. Proc Natl Acad Sci USA. 94:1997;3151-3155.
36. Lei M, Kawasaki Y, Young MR, Kihara M, Sugino A, Tye BK Mcm2 is a target of regulation by Cdc7-Dbf4 during the initiation of DNA synthesis. Genes Dev. 11:1997;3365-3374. Allele-specific suppression of mcm2 mutants by dbf4 was observed. The two proteins were shown to physically interact by two-hybrid analysis and affinity chromatography. Recombinant Cdc7-Dbf4 kinase was shown to efficiently phosphorylate Mcm2 and Mcm6 in vitro. These results suggest that Mcm2 is probably a major target for the Cdc7-Dbf4 kinase in vivo.
37. McKie JM, Wadey RB, Sutherland HF, Taylor CL, Scambler PJ Direct selection of conserved cDNAs from the DiGeorge critical region: isolation of a novel CDC45-like gene. Genome Res. 8:1998;834-841.
38. Saha P, Thome KC, Yamaguchi R, Hou Z, Weremowicz S, Dutta A The human homolog of Saccharomyces cerevisiae CDC45. J Biol Chem. 273:1998;18205-18209.
39. Miyake S, Yamashita S Identification of sna41 gene, which is the suppressor of nda4 mutation and is involved in DNA replication in Schizosaccharomyces pombe. Genes Cells. 3:1998;157-166.
40. Hopwood B, Dalton S Cdc45p assembles into a complex with Cdc46p/Mcm5p, is required for minichromosome maintenance, and is essential for chromosomal DNA replication. Proc Natl Acad Sci USA. 93:1996;12309-12314.
41. Zou L, Mitchell J, Stillman B CDC45, a novel yeast gene that functions with the origin recognition complex and Mcm proteins in initiation of DNA replication. Mol Cell Biol. 17:1997;553-563.
42. Owens JC, Detweiler CS, Li JJ CDC45 is required in conjunction with CDC7/DBF4 to trigger the initiation of DNA replication. Proc Natl Acad Sci USA. 94:1997;12521-12526. Cdc45 is shown to be required for S phase after execution of START. Data from reciprocal shift experiments suggest that the functions of Cdc45 and Cdc7 are interdependent and cannot occur sequentially.
43. 1 and S phase. The association with chromatin is dependent on the function of Cdc6 and Mcm2, as well as functional Cdks but not on the activity of Cdc7. These results suggest that Cdc45 may act as a direct or indirect target of the Cdk signal that triggers initiation.
44. Hayles J, Fisher D, Woollard A, Nurse P Temporal order of S phase and mitosis in fission yeast is determined by the state of the p34(cdc2) mitotic B cyclin complex. Cell. 78:1994;813-822.
45. Dahmann C, Diffley JF, Nasmyth KA S-phase-promoting cyclin-dependent kinases prevent re-replication by inhibiting the transition of replication origins to a pre-replicative state. Curr Biol. 5:1995;1257-1269.
46. 1 after CDC6, relatively normal DNA replication was observed, consistent with the idea that Cdks do not disassemble pre-replicative complexes once they have formed.
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48. Nishitani H, Nurse P p65(cdc18) plays a major role controlling the initiation of DNA replication in fission yeast. Cell. 83:1995;397-405.
49. 2 is dependent on the amino-terminal 47 amino acids of Cdc6. This domain interacts in a 2-hybrid screen with the Cdc4 protein, which is involved in ubiquitin-mediated protein degradation; consistent with this, Cdc6 protein becomes stabilised in cdc4 mutants. Interestingly, stabilisation of Cdc6 by removal of the amino-terminal domain does not perturb the cell cycle, suggesting that Cdc6 degradation is not essential for preventing re-replication of DNA in a single cell cycle.
50. 2 re-establishes pol-α association with chromatin, suggesting that it is negatively regulated by Cdks.
51. 2 and M phases but is degraded in late mitosis by the anaphase promoting complex. Geminin inhibits DNA replication by blocking the assembly of MCM/P1 proteins onto chromatin. Although no effect on replication was observed when Xenopus extracts were immunodepleted of geminin, it nevertheless probably contributes to mechanisms that prevent re-replication of DNA in a single cell cycle.
52. Strehl S, LaSalle JM, Lalande M High-resolution analysis of DNA replication domain organization across an R/G-band boundary. Mol Cell Biol. 17:1997;6157-6166. The replication timing of different sequences throughout 5 Mb of human chromosome 13q was analysed. A gradient of replication timing was observed, extending from the early-replicating R band, into the late-replicating G band. This suggests that chromosomal context represents an important determinant for the time of origin firing in S phase.
53. Ferguson BM, Brewer BJ, Reynolds AE, Fangman WL A yeast origin of replication is activated late in S phase. Cell. 65:1991;507-515.
54. Friedman KL, Diller JD, Ferguson BM, Nyland SVM, Brewer BJ, Fangman WL Multiple determinants controlling activation of yeast replication origins late in S phase. Genes Dev. 10:1996;1595-1607.
55. Wei X, Samarabandu J, Devdhar RS, Siegel AJ, Acharya R, Berezney R Segregation of transcription and replication sites into higher order domains. Science. 281:1998;1502-1506. Sites of transcription and replication were simultaneously labelled. There was little overlap in the resulting signals at any stage during S phase, suggesting that these processes take place at spatially distinct locations. The authors propose that the nucleus is divided into separate transcription and replication zones, which are modified as S phase progresses to allow replication of all the DNA.
56. Spann TP, Moir RD, Goldman AE, Stick R, Goldman RD Disruption of nuclear lamin organization alters the distribution of replication factors and inhibits DNA synthesis. J Cell Biol. 136:1997;1201-1212.
57. Walter J, Sun L, Newport J Regulated chromosomal DNA replication in the absence of a nucleus. Mol Cell. 1:1998;519-529. Low-speed supernatants of Xenopus egg extracts assemble DNA into interphase nuclei and then replicate it. This paper describes a further development of the cell-free system where nuclear assembly is no longer required for DNA replication. First, DNA templates are incubated in cytoplasmic extracts to allow licensing to occur. A concentrated nuclear extract is then added and this leads to the efficient initiation and completion of DNA replication. Only a single round of DNA replication occurs under these conditions because the nuclear extract also contains an inhibitor of the licensing reaction.
58. 1 and can also be seen in micronuclei containing only one or two chromosomes.
59. Gotta M, Laroche T, Formenton A, Maillet L, Scherthan H, Gasser SM The clustering of telomeres and colocalization with Rap1, Sir3, and Sir4 proteins in wild-type Saccharomyces cerevisiae. J Cell Biol. 134:1996;1349-1363.
60. Raghuraman MK, Brewer BJ, Fangman WL Cell cycle-dependent establishment of a late replication program. Science. 276:1997;806-809.
61. Epstein CB, Cross FR CLB5: a novel B cyclin from budding yeast with a role in S phase. Genes Dev. 6:1992;1695-1706.
62. Kühne C, Linder P A new pair of B-type cyclins from Saccharomyces cerevisiae that function early in the cell cycle. EMBO J. 12:1993;3437-3447.
63. Schwob E, Nasmyth K CLB5 and CLB6, a new pair of B-Cyclins involved in DNA replication in Saccharomyces cerevisiae. Gene Dev. 7:1993;1160-1175.
64. Donaldson AD, Raghuraman MK, Friedman KL, Cross FR, Brewer BJ, Fangman WL CLB5-dependent activation of late replication origins in S. cerevisiae. Mol Cell. 2:1998;173-182. An investigation of the requirement for the S-phase promoting cyclins, Clb5 and Clb6, for firing of early- and late-replication origins. The results suggest that Cdc28-Clb5 can fire both early and late origins, whereas Cdc28-Clb6 can only fire late origins. In the absence of both Clb5 and Clb6, S-phase onset is delayed; however, the mitotic cyclins (Clb1-4) can substitute by firing both early and late origins, so that S phase proceeds normally once it has begun.
65. ••].
66. ••] investigate the response of cells to hydroxy urea and MMS, two agents that impede replication fork progression. Treatment with either inhibitor causes a block to late replication origin firing, as assayed by origin footprinting or gel analysis of replication intermediates. This block is an active process mediated by both Rad53 and Orc2, as cells lacking either of these proteins fire their late origins when fork progression is impeded. Late origin firing time is slightly advanced in a rad53 mutant in an undisturbed S phase, suggesting that the role of Rad53 may be more complex than that of a simple checkpoint.
67. Tanaka T, Nasmyth K Association of RPA with chromosomal replication origins requires an Mcm protein, and is regulated by Rad53, and cyclin- and Dbf4-dependent kinases. EMBO J. 17:1998;5182-5191. A CHIP study showing that both Cdk-cyclin and Cdc7 activities are required for assembly of a subunit of the single-stranded DNA-binding protein RPA onto origins. Primase association with replication origins depends in turn upon RPA loading. Addition of hydroxyurea (to slow replication fork progress) was required to observe these interations. Rad53 is required to prevent RPA loading at late origins when S-phase progress is blocked by hydroxyxurea.
68. Desany BA, Alcasabas AA, Bachant JB, Elledge SJ Recovery from DNA replicational stress is the essential function of the S-phase checkpoint pathway. Genes Dev. 12:1998;2956-2970. RAD53 and MEC1 are essential genes that are required for checkpoint function in S. cerevisiae. This paper shows that the essential requirement for RAD53 is for the successful completion of chromosome replication and that this does not depend on its known checkpoint function. The requirement for RAD53 and MEC1 can be suppressed by expression of RNR1, the large subunit of ribonucleotide reductase, suggesting that their essential function is to maintain adequate dNTP levels and that this pathway is required during every S phase.