, Volume 120, Issue 1, pp 39–46 | Cite as

Regulation of DNA replication by chromatin structures: accessibility and recruitment

  • Makoto T. Hayashi
  • Hisao MasukataEmail author


The initiation of DNA replication and the elongation of DNA strands take place in chromatin, a huge compound DNA–protein complex. Although the factors involved in the process of DNA replication have been largely elucidated, the underlying mechanisms that determine their behavior in the context of chromatin have only recently begun to be understood. It has been known that transcription is tightly regulated by the state of chromatin compaction, which governs the accessibility of DNA to trans-acting factors. This process is influenced by several determinants of chromatin structure, including intrinsic nucleosome positioning, the nucleosome remodeling complex, histone post-translational modifiers, and histone- and DNA-binding proteins. Growing evidence indicates that this concept is also applicable to the regulation of DNA replication. In addition, recent studies have demonstrated a distinctive mode of regulation. Some non-histone chromatin-binding proteins have been shown to interact physically with replication factors, thereby facilitating their recruitment at specific chromosomal loci. This type of regulation may allow control of local replication activity without affecting other chromosomal processes.


Chromatin Structure Fission Yeast Replication Origin Nucleosome Position Replication Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by a grant-in-aid from the Japan Society for the Promotion of Science Fellows and the Human Frontier Science Program Fellowship to M.T.H. and by a grant-in-aid from the Ministry of Education, Science, Technology, Sport, and Culture, Japan, to H.M. We are grateful to Jun-ichi Nakayama, Takuro Nakagawa, and Tatsuro S. Takahashi for ideas and comments.


  1. 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 22:4294–4303CrossRefPubMedGoogle Scholar
  2. Aladjem MI (2007) Replication in context: dynamic regulation of DNA replication patterns in metazoans. Nat Rev Genet 8:588–600CrossRefPubMedGoogle Scholar
  3. Alexiadis V, Varga-Weisz PD, Bonte E, Becker PB, Gruss C (1998) In vitro chromatin remodelling by chromatin accessibility complex (CHRAC) at the SV40 origin of DNA replication. EMBO J 17:3428–3438CrossRefPubMedGoogle Scholar
  4. Aparicio JG, Viggiani CJ, Gibson DG, Aparicio OM (2004) The Rpd3-Sin3 histone deacetylase regulates replication timing and enables intra-S origin control in Saccharomyces cerevisiae. Mol Cell Biol 24:4769–4780CrossRefPubMedGoogle Scholar
  5. Atanasiu C, Deng Z, Wiedmer A, Norseen J, Lieberman PM (2006) ORC binding to TRF2 stimulates OriP replication. EMBO Rep 7:716–721CrossRefPubMedGoogle Scholar
  6. Austin RJ, Orr-Weaver TL, Bell SP (1999) Drosophila ORC specifically binds to ACE3, an origin of DNA replication control element. Genes Dev 13:2639–2649CrossRefPubMedGoogle Scholar
  7. Auth T, Kunkel E, Grummt F (2006) Interaction between HP1alpha and replication proteins in mammalian cells. Exp Cell Res 312:3349–3359CrossRefPubMedGoogle Scholar
  8. Bell SP, Dutta A (2002) DNA replication in eukaryotic cells. Annu Rev Biochem 71:333–374CrossRefPubMedGoogle Scholar
  9. Cairns B (2009) The logic of chromatin architecture and remodelling at promoters. Nature 461:193–198CrossRefPubMedGoogle Scholar
  10. 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 96:2656–2661CrossRefPubMedGoogle Scholar
  11. Crampton A, Chang F, Pappas DL, Frisch RL, Weinreich M (2008) An ARS element inhibits DNA replication through a SIR2-dependent mechanism. Mol Cell 30:156–166CrossRefPubMedGoogle Scholar
  12. Demeret C, Vassetzky Y, Méchali M (2001) Chromatin remodelling and DNA replication: from nucleosomes to loop domains. Oncogene 20:3086–3093CrossRefPubMedGoogle Scholar
  13. Deng Z, Dheekollu J, Broccoli D, Dutta A, Lieberman PM (2007) The origin recognition complex localizes to telomere repeats and prevents telomere-circle formation. Curr Biol 17:1989–1995CrossRefPubMedGoogle Scholar
  14. Deng Z, Norseen J, Wiedmer A, Riethman H, Lieberman PM (2009) TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell 35:403–413CrossRefPubMedGoogle Scholar
  15. Depamphilis M (2005) Cell cycle dependent regulation of the origin recognition complex. Cell Cycle 4:70–79CrossRefPubMedGoogle Scholar
  16. Diffley JFX (2004) Regulation of early events in chromosome replication. Curr Biol 14:R778–R786CrossRefPubMedGoogle Scholar
  17. Diffley JFX, Cocker JH, Dowell SJ, Rowley A (1994) Two steps in the assembly of complexes at yeast replication origins in vivo. Cell 78:303–316CrossRefPubMedGoogle Scholar
  18. Dueber ELC, Corn JE, Bell SD, Berger JM (2007) Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex. Science 317:1210–1213CrossRefPubMedGoogle Scholar
  19. Eaton ML, Galani K, Kang S, Bell SP, Macalpine DM (2010) Conserved nucleosome positioning defines replication origins. Genes Dev 24:748–753CrossRefPubMedGoogle Scholar
  20. Fanti L, Pimpinelli S (2008) HP1: a functionally multifaceted protein. Curr Opin Genet Dev 18:169–174CrossRefPubMedGoogle Scholar
  21. Field Y, Kaplan N, Fondufe-Mittendorf Y, Moore IK, Sharon E, Lubling Y, Widom J, Segal E (2008) Distinct modes of regulation by chromatin encoded through nucleosome positioning signals. PLoS Comput Biol 4:e1000216CrossRefPubMedGoogle Scholar
  22. Flanagan JF, Peterson CL (1999) A role for the yeast SWI/SNF complex in DNA replication. Nucleic Acids Res 27:2022–2028CrossRefPubMedGoogle Scholar
  23. Fox CA, Weinreich M (2008) Beyond heterochromatin: SIR2 inhibits the initiation of DNA replication. Cell Cycle 7:3330–3334CrossRefPubMedGoogle Scholar
  24. Francis LI, Randell JCW, Takara TJ, Uchima L, Bell SP (2009) Incorporation into the prereplicative complex activates the Mcm2–7 helicase for Cdc7–Dbf4 phosphorylation. Genes Dev 23:643–654CrossRefPubMedGoogle Scholar
  25. Gaudier M, Schuwirth BS, Westcott SL, Wigley DB (2007) Structural basis of DNA replication origin recognition by an ORC protein. Science 317:1213–1216CrossRefPubMedGoogle Scholar
  26. Gilbert DM (2001) Making sense of eukaryotic DNA replication origins. Science 294:96–100CrossRefPubMedGoogle Scholar
  27. Gilbert DM (2002) Replication timing and transcriptional control: beyond cause and effect. Curr Opin Cell Biol 14:377–383CrossRefPubMedGoogle Scholar
  28. Goren A, Tabib A, Hecht M, Cedar H (2008) DNA replication timing of the human beta-globin domain is controlled by histone modification at the origin. Genes Dev 22:1319–1324CrossRefPubMedGoogle Scholar
  29. Grewal SIS, Jia S (2007) Heterochromatin revisited. Nat Rev Genet 8:35–46CrossRefPubMedGoogle Scholar
  30. Groth A, Rocha W, Verreault A, Almouzni G (2007) Chromatin challenges during DNA replication and repair. Cell 128:721–733CrossRefPubMedGoogle Scholar
  31. Hayashi MT, Takahashi TS, Nakagawa T, Nakayama J, Masukata H (2009) The heterochromatin protein Swi6/HP1 activates replication origins at the pericentromeric region and silent mating-type locus. Nat Cell Biol 11:357–362CrossRefPubMedGoogle Scholar
  32. Hediger F, Gasser SM (2006) Heterochromatin protein 1: don't judge the book by its cover! Curr Opin Genet Dev 16:143–150CrossRefPubMedGoogle Scholar
  33. Hiratani I, Leskovar A, Gilbert DM (2004) Differentiation-induced replication-timing changes are restricted to AT-rich/long interspersed nuclear element (LINE)-rich isochores. Proc Natl Acad Sci USA 101:16861–16866CrossRefPubMedGoogle Scholar
  34. Hiratani I, Takebayashi S, Lu J, Gilbert DM (2009) Replication timing and transcriptional control: beyond cause and effect—part II. Curr Opin Genet Dev 19:142–149CrossRefPubMedGoogle Scholar
  35. Huang DW, Fanti L, Pak DTS, 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 142:307–318CrossRefPubMedGoogle Scholar
  36. Kaplan N, Moore IK, Fondufe-Mittendorf Y, Gossett AJ, Tillo D, Field Y, Leproust EM, Hughes TR, Lieb JD, Widom J, Segal E (2009) The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458:362–366CrossRefPubMedGoogle Scholar
  37. Knott SRV, Viggiani CJ, Tavaré S, Aparicio OM (2009) Genome-wide replication profiles indicate an expansive role for Rpd3L in regulating replication initiation timing or efficiency, and reveal genomic loci of Rpd3 function in Saccharomyces cerevisiae. Genes Dev 23:1077–1090CrossRefPubMedGoogle Scholar
  38. Kong D, Coleman TR, Depamphilis ML (2003) Xenopus origin recognition complex (ORC) initiates DNA replication preferentially at sequences targeted by Schizosaccharomyces pombe ORC. EMBO J 22:3441–3450CrossRefPubMedGoogle Scholar
  39. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705CrossRefPubMedGoogle Scholar
  40. 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 22:1036–1048CrossRefPubMedGoogle Scholar
  41. Lantermann AB, Straub T, Strålfors A, Yuan G-C, Ekwall K, Korber P (2010) Schizosaccharomyces pombe genome-wide nucleosome mapping reveals positioning mechanisms distinct from those of Saccharomyces cerevisiae. Nat Struct Mol Biol 17:251–257CrossRefPubMedGoogle Scholar
  42. Leatherwood J, Vas A (2003) Connecting ORC and heterochromatin: why? Cell Cycle 2:573–575CrossRefPubMedGoogle Scholar
  43. Lidonnici MR, Rossi R, Paixão 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 117:5221–5231CrossRefPubMedGoogle Scholar
  44. Lindner SE, Zeller K, Schepers A, Sugden B (2008) The affinity of EBNA1 for its origin of DNA synthesis is a determinant of the origin's replicative efficiency. J Virol 82:5693–5702CrossRefPubMedGoogle Scholar
  45. Lipford JR, Bell SP (2001) Nucleosomes positioned by ORC facilitate the initiation of DNA replication. Mol Cell 7:21–30CrossRefPubMedGoogle Scholar
  46. MacAlpine DM, Bell SP (2005) A genomic view of eukaryotic DNA replication. Chromosome Res 13:309–326CrossRefPubMedGoogle Scholar
  47. MacAlpine DM, Rodríguez HK, Bell SP (2004) Coordination of replication and transcription along a Drosophila chromosome. Genes Dev 18:3094–3105CrossRefPubMedGoogle Scholar
  48. 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 20:201–211CrossRefPubMedGoogle Scholar
  49. Miotto B, Struhl K (2008) HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1. Genes Dev 22:2633–2638CrossRefPubMedGoogle Scholar
  50. Miotto B, Struhl K (2010) HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by geminin. Mol Cell 37:57–66CrossRefPubMedGoogle Scholar
  51. Narlikar GJ, Fan H-Y, Kingston RE (2002) Cooperation between complexes that regulate chromatin structure and transcription. Cell 108:475–487CrossRefPubMedGoogle Scholar
  52. Nieduszynski CA, Knox Y, Donaldson AD (2006) Genome-wide identification of replication origins in yeast by comparative genomics. Genes Dev 20:1874–1879CrossRefPubMedGoogle Scholar
  53. Norseen J, Thomae A, Sridharan V, Aiyar A, Schepers A, Lieberman PM (2008) RNA-dependent recruitment of the origin recognition complex. EMBO J 27:3024–3035CrossRefPubMedGoogle Scholar
  54. Pak DTS, 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 91:311–323CrossRefPubMedGoogle Scholar
  55. Pasero P, Schwob E (2000) Think global, act local—how to regulate S phase from individual replication origins. Curr Opin Genet Dev 10:178–186CrossRefPubMedGoogle Scholar
  56. Patel PK, Kommajosyula N, Rosebrock A, Bensimon A, Leatherwood J, Bechhoefer J, Rhind N (2008) The Hsk1(Cdc7) replication kinase regulates origin efficiency. Mol Biol Cell 19:5550–5558CrossRefPubMedGoogle Scholar
  57. Prasanth SG, Prasanth KV, Siddiqui K, Spector DL, Stillman B (2004) Human Orc2 localizes to centrosomes, centromeres and heterochromatin during chromosome inheritance. EMBO J 23:2651–2663CrossRefPubMedGoogle Scholar
  58. Remus D, Beall EL, Botchan MR (2004) DNA topology, not DNA sequence, is a critical determinant for Drosophila ORC–DNA binding. EMBO J 23:897–907CrossRefPubMedGoogle Scholar
  59. Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JFX (2010) Concerted loading of Mcm2–7 double hexamers around DNA during DNA replication origin licensing. Cell 139:719–730CrossRefGoogle Scholar
  60. Ruthenburg A, Li H, Patel DJ, David Allis C (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8:983–994CrossRefPubMedGoogle Scholar
  61. Saha A, Wittmeyer J, Cairns BR (2006) Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 7:437–447CrossRefPubMedGoogle Scholar
  62. Schwaiger M, Schübeler D (2006) A question of timing: emerging links between transcription and replication. Curr Opin Genet Dev 16:177–183CrossRefPubMedGoogle Scholar
  63. Schwaiger M, Kohler H, Oakeley EJ, Stadler MB, Schubeler D (2010) Heterochromatin protein 1 (HP1) modulates replication timing of the Drosophila genome. Genome Res 20:771–780CrossRefPubMedGoogle Scholar
  64. Sclafani RA, Holzen TM (2007) Cell cycle regulation of DNA replication. Annu Rev Genet 41:237–280CrossRefPubMedGoogle Scholar
  65. Segal E, Widom J (2009) Poly(dA:dT) tracts: major determinants of nucleosome organization. Curr Opin Struct Biol 19:65–71CrossRefPubMedGoogle Scholar
  66. Segurado M, de Luis A, Antequera F (2003) Genome-wide distribution of DNA replication origins at A + T-rich islands in Schizosaccharomyces pombe. EMBO Rep 4:1048–1053CrossRefPubMedGoogle Scholar
  67. Sequeira-Mendes J, Díaz-Uriarte R, Apedaile A, Huntley D, Brockdorff N, Gómez M, Bickmore W (2009) Transcription initiation activity sets replication origin efficiency in mammalian cells. PLoS Genet 5:e1000446CrossRefPubMedGoogle Scholar
  68. Sfeir A, Kosiyatrakul ST, Hockemeyer D, MacRae SL, Karlseder J, Schildkraut CL, de Lange T (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138:90–103CrossRefPubMedGoogle Scholar
  69. Sheu Y-J, Stillman B (2010) The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature 463:113–117CrossRefPubMedGoogle Scholar
  70. Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL (2006) Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311:844–847CrossRefPubMedGoogle Scholar
  71. Simpson RT (1990) Nucleosome positioning can affect the function of a cis-acting DNA element in vivo. Nature 343:387–389CrossRefPubMedGoogle Scholar
  72. Smallwood A, Black JC, Tanese N, Pradhan S, Carey M (2008) HP1-mediated silencing targets Pol II coactivator complexes. Nat Struct Mol Biol 15:318–320CrossRefPubMedGoogle Scholar
  73. Stanojcic S, Lemaitre J-M, Brodolin K, Danis E, Mechali M (2008) In Xenopus egg extracts, DNA replication initiates preferentially at or near asymmetric AT sequences. Mol Cell Biol 28:5265–5274CrossRefPubMedGoogle Scholar
  74. 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 22:964–974CrossRefPubMedGoogle Scholar
  75. Tanaka S, Umemori T, Hirai K, Muramatsu S, Kamimura Y, Araki H (2007) CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast. Nature 445:328–332CrossRefPubMedGoogle Scholar
  76. Taverna SD, Li H, Ruthenburg AJ, David Allis C, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14:1025–1040CrossRefPubMedGoogle Scholar
  77. 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 17:1894–1908CrossRefPubMedGoogle Scholar
  78. Vogelauer M, Rubbi L, Lucas I, Brewer BJ, Grunstein M (2002) Histone acetylation regulates the time of replication origin firing. Mol Cell 10:1223–1233CrossRefPubMedGoogle Scholar
  79. Wang L, Lin C-M, Brooks S, Cimbora D, Groudine M, Aladjem MI (2004) The human beta-globin replication initiation region consists of two modular independent replicators. Mol Cell Biol 24:3373–3386CrossRefPubMedGoogle Scholar
  80. Weinreich M, Palacios DeBeer MA, Fox CA (2004) The activities of eukaryotic replication origins in chromatin. Biochim Biophys Acta 1677:142–157PubMedGoogle Scholar
  81. White EJ, Emanuelsson O, Scalzo D, Royce T, Kosak S, Oakeley EJ, Weissman S, Gerstein M, Groudine M, Snyder M, Schubeler D (2004) DNA replication-timing analysis of human chromosome 22 at high resolution and different developmental states. Proc Natl Acad Sci USA 101:17771–17776CrossRefPubMedGoogle Scholar
  82. Wu P-YJ, Nurse P (2009) Establishing the program of origin firing during S phase in fission yeast. Cell 136:852–864CrossRefPubMedGoogle Scholar
  83. Wu R, Singh PB, Gilbert DM (2006) Uncoupling global and fine-tuning replication timing determinants for mouse pericentric heterochromatin. J Cell Biol 174:185–194CrossRefPubMedGoogle Scholar
  84. Zegerman P, Diffley JFX (2007) Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast. Nature 445:281–285CrossRefPubMedGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Biological Sciences, Graduate School of ScienceOsaka UniversityOsakaJapan
  2. 2.The Salk Institute for Biological StudiesLa JollaUSA

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