Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Order from clutter: selective interactions at mammalian replication origins

Nature Reviews Genetics volume 18, pages 101–116 (2017)Cite this article

Subjects

Key Points

  • Metazoan cells contain cis-acting DNA sequences, called replicators, that do not share a single consensus DNA sequence but are required for the initiation of DNA replication.

  • Instead of a single interaction with a consensus sequence, groups of replication origins exhibit multiple DNA–protein interactions and associate with distinct chromatin modifications that modulate the frequency of replication initiation.

  • Metazoans exhibit a flexible initiation programme, initiating replication intermittently from alternate replication origins.

  • Flexible initiation is essential for genomic stability in the face of perturbation of DNA replication and is facilitated by a surplus of pre-replication complexes.

  • Simulation studies can predict the order of replication initiation — the replication-timing programme — solely on the basis of the locations of active replication origins.

  • Cell-specific chromatin architecture is key for both replication origin activation and replication timing, and DNA synthesis can proceed in a consistent order without requiring specific interactions to dictate replication timing.

Abstract

Mammalian chromosome duplication progresses in a precise order and is subject to constraints that are often relaxed in developmental disorders and malignancies. Molecular information about the regulation of DNA replication at the chromatin level is lacking because protein complexes that initiate replication seem to bind chromatin indiscriminately. High-throughput sequencing and mathematical modelling have yielded detailed genome-wide replication initiation maps. Combining these maps and models with functional genetic analyses suggests that distinct DNA–protein interactions at subgroups of replication initiation sites (replication origins) modulate the ubiquitous replication machinery and supports an emerging model that delineates how indiscriminate DNA-binding patterns translate into a consistent, organized replication programme.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Organization of replication origins, replicons and replication-timing domains.
Figure 2: Genetic and epigenetic features of replication origins.
Figure 3: Long-range chromatin interactions can regulate origin activation and replication timing.
Figure 4: Replication origin choice and origin dormancy.
Figure 5: Origin inhibition and activation in unperturbed cells and after replication stress.

Similar content being viewed by others

References

  1. Inaki, K. & Liu, E. T. Structural mutations in cancer: mechanistic and functional insights. Trends Genet. 28, 550–559 (2012).

    CAS  PubMed  Google Scholar 

  2. Abbas, T., Keaton, M. A. & Dutta, A. Genomic instability in cancer. Cold Spring Harb. Perspect. Biol. 5, a012914 (2013).

    PubMed  PubMed Central  Google Scholar 

  3. Brosh, R. M. Jr. DNA helicases involved in DNA repair and their roles in cancer. Nat. Rev. Cancer 13, 542–558 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sousa, F. G. et al. Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity. DNA Repair (Amst.) 28, 107–115 (2015).

    CAS  Google Scholar 

  5. Lange, S. S., Takata, K. & Wood, R. D. DNA polymerases and cancer. Nat. Rev. Cancer 11, 96–110 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Fragkos, M., Ganier, O., Coulombe, P. & Mechali, M. DNA replication origin activation in space and time. Nat. Rev. Mol. Cell Biol. 16, 360–374 (2015).

    CAS  PubMed  Google Scholar 

  7. Rivera-Mulia, J. C. & Gilbert, D. M. Replicating large genomes: divide and conquer. Mol. Cell 62, 756–765 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Mechali, M. Eukaryotic DNA replication origins: many choices for appropriate answers. Nat. Rev. Mol. Cell Biol. 11, 728–738 (2010).

    CAS  PubMed  Google Scholar 

  9. Masai, H., Matsumoto, S., You, Z., Yoshizawa-Sugata, N. & Oda, M. Eukaryotic chromosome DNA replication: where, when, and how? Annu. Rev. Biochem. 79, 89–130 (2010).

    CAS  PubMed  Google Scholar 

  10. Aladjem, M. I. Replication in context: dynamic regulation of DNA replication patterns in metazoans. Nat. Rev. Genet. 8, 588–600 (2007).

    CAS  PubMed  Google Scholar 

  11. Bartholdy, B., Mukhopadhyay, R., Lajugie, J., Aladjem, M. I. & Bouhassira, E. E. Allele-specific analysis of DNA replication origins in mammalian cells. Nat. Commun. 6, 7051 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Pope, B. D. et al. Topologically associating domains are stable units of replication-timing regulation. Nature 515, 402–405 (2014). This study showed that megabase-scale chromatin domains, which exhibit almost synchronous replication during S phase, align with chromatin domains that favour internal chromatin interactions, suggesting that the order of replication delineates specific chromosomal structures.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gindin, Y., Valenzuela, M. S., Aladjem, M. I., Meltzer, P. S. & Bilke, S. A chromatin structure-based model accurately predicts DNA replication timing in human cells. Mol. Syst. Biol. 10, 722 (2014). This simulation study based on a simple model of replication kinetics was able to predict experimental replication-timing profiles using DNAse 1-hypersensitive sites as an approximation of initiation sites, necessitating no explicit timing information.

    PubMed  PubMed Central  Google Scholar 

  14. Martin, M. M. et al. Genome-wide depletion of replication initiation events in highly transcribed regions. Genome Res. 21, 1822–1832 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Marks, A. B., Smith, O. K. & Aladjem, M. I. Replication origins: determinants or consequences of nuclear organization? Curr. Opin. Genet. Dev. 37, 67–75 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Besnard, E. et al. Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs. Nat. Struct. Mol. Biol. 19, 837–844 (2012).

    CAS  PubMed  Google Scholar 

  17. Mechali, M., Yoshida, K., Coulombe, P. & Pasero, P. Genetic and epigenetic determinants of DNA replication origins, position and activation. Curr. Opin. Genet. Dev. 23, 124–131 (2013).

    CAS  PubMed  Google Scholar 

  18. Das, S. P. et al. Replication timing is regulated by the number of MCMs loaded at origins. Genome Res. 25, 1886–1892 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lob, D. et al. 3D replicon distributions arise from stochastic initiation and domino-like DNA replication progression. Nat. Commun. 7, 11207 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Vashee, S. et al. Sequence-independent DNA binding and replication initiation by the human origin recognition complex. Genes Dev. 17, 1894–1908 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. MacAlpine, H. K., Gordan, R., Powell, S. K., Hartemink, A. J. & MacAlpine, D. M. Drosophila ORC localizes to open chromatin and marks sites of cohesin complex loading. Genome Res. 20, 201–211 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Miotto, B., Ji, Z. & Struhl, K. Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers. Proc. Natl Acad. Sci. USA 113, E4810–E4819 (2016).

    CAS  PubMed  Google Scholar 

  23. Dellino, G. I. et al. Genome-wide mapping of human DNA-replication origins: levels of transcription at ORC1 sites regulate origin selection and replication timing. Genome Res. 23, 1–11 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cayrou, C. et al. The chromatin environment shapes DNA replication origin organization and defines origin classes. Genome Res. 25, 1873–1885 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Rivera-Mulia, J. C. & Gilbert, D. M. Replication timing and transcriptional control: beyond cause and effect — part III. Curr. Opin. Cell Biol. 40, 168–178 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Prioleau, M. N. & MacAlpine, D. M. DNA replication origins — where do we begin? Genes Dev. 30, 1683–1697 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Rhind, N. & Gilbert, D. M. DNA replication timing. Cold Spring Harb. Perspect. Med. 3, 1–26 (2013).

    Google Scholar 

  28. Renard-Guillet, C., Kanoh, Y., Shirahige, K. & Masai, H. Temporal and spatial regulation of eukaryotic DNA replication: from regulated initiation to genome-scale timing program. Semin. Cell Dev. Biol. 30, 110–120 (2014).

    CAS  PubMed  Google Scholar 

  29. Eaton, M. L. et al. Chromatin signatures of the Drosophila replication program. Genome Res. 21, 164–174 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Jacob, F., Brenner, J. & Cuzin, F. On the regulation of DNA replication in bacteria. Cold Spring Harb. Symp. Quant. Biol. 28, 329–348 (1963). The replicon model described in this paper continues to form the basis of our current thinking on the regulation of genome duplication, although some modifications have been made.

    CAS  Google Scholar 

  31. Yasuda, S. & Hirota, Y. Cloning and mapping of the replication origin of Escherichia coli. Proc. Natl Acad. Sci. USA 74, 5458–5462 (1977).

    CAS  PubMed  Google Scholar 

  32. Eichenlaub, R., Figurski, D. & Helinski, D. R. Bidirection replication from a unique origin in a mini-F plasmid. Proc. Natl Acad. Sci. USA 74, 1138–1141 (1977).

    CAS  PubMed  Google Scholar 

  33. Struhl, K., Stinchcomb, D. T., Scherer, S. & Davis, R. W. High-frequency transformation of yeast: autonomous replication of hybrid DNA molecules. Proc. Natl Acad. Sci. USA 76, 1035–1039 (1979).

    CAS  PubMed  Google Scholar 

  34. Aladjem, M. I., Rodewald, L. W., Kolman, J. L. & Wahl, G. M. Genetic dissection of a mammalian replicator in the human β-globin locus. Science 281, 1005–1009 (1998). This study showed that replicators can induce sequence-specific initiation of DNA replication when placed at ectopic sites, demonstrating the regulation of DNA replication by cis -acting elements in mammalian cells.

    CAS  PubMed  Google Scholar 

  35. Altman, A. L. & Fanning, E. Defined sequence modules and an architectural element cooperate to promote initiation at an ectopic mammalian chromosomal replication origin. Mol. Cell. Biol. 24, 4138–4150 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu, G., Malott, M. & Leffak, M. Multiple functional elements comprise a mammalian chromosomal replicator. Mol. Cell. Biol. 23, 1832–1842 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Paixao, S. et al. Modular structure of the human lamin B2 replicator. Mol. Cell. Biol. 24, 2958–2967 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Remus, D. & Diffley, J. F. Eukaryotic DNA replication control: lock and load, then fire. Curr. Opin. Cell Biol. 21, 771–777 (2009).

    CAS  PubMed  Google Scholar 

  39. Bolon, Y. T. & Bielinsky, A. K. The spatial arrangement of ORC binding modules determines the functionality of replication origins in budding yeast. Nucleic Acids Res. 34, 5069–5080 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Remus, D., Beall, E. L. & Botchan, M. R. DNA topology, not DNA sequence, is a critical determinant for Drosophila ORC–DNA binding. EMBO J. 23, 897–907 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Das, S. P. & Rhind, N. How and why multiple MCMs are loaded at origins of DNA replication. Bioessays 38, 613–617 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hashizume, T. & Shimizu, N. Dissection of mammalian replicators by a novel plasmid stability assay. J. Cell. Biochem. 101, 552–565 (2007).

    CAS  PubMed  Google Scholar 

  43. Guan, Z. et al. Decreased replication origin activity in temporal transition regions. J. Cell Biol. 187, 623–635 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Urban, J. M., Foulk, M. S., Casella, C. & Gerbi, S. A. The hunt for origins of DNA replication in multicellular eukaryotes. F1000Prime Rep. 7, 30 (2015).

    PubMed  PubMed Central  Google Scholar 

  45. Hyrien, O. Peaks cloaked in the mist: the landscape of mammalian replication origins. J. Cell Biol. 208, 147–160 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Petryk, N. et al. Replication landscape of the human genome. Nat. Commun. 7, 10208 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Huppert, J. L. & Balasubramanian, S. Prevalence of quadruplexes in the human genome. Nucleic Acids Res. 33, 2908–2916 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Smith, O. K. et al. Distinct epigenetic features of differentiation-regulated replication origins. Epigenetics Chromatin 9, 18 (2016).

    PubMed  PubMed Central  Google Scholar 

  49. Sherstyuk, V. V., Shevchenko, A. I. & Zakian, S. M. Epigenetic landscape for initiation of DNA replication. Chromosoma 123, 183–199 (2014).

    CAS  PubMed  Google Scholar 

  50. Kanoh, Y. et al. Rif1 binds to G quadruplexes and suppresses replication over long distances. Nat. Struct. Mol. Biol. 22, 889–897 (2015).

    CAS  PubMed  Google Scholar 

  51. Chen, X., Liu, G. & Leffak, M. Activation of a human chromosomal replication origin by protein tethering. Nucleic Acids Res. 41, 6460–6474 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Fu, H. et al. Preventing gene silencing with human replicators. Nat. Biotechnol. 24, 572–576 (2006).

    CAS  PubMed  Google Scholar 

  53. Conner, A. L. & Aladjem, M. I. The chromatin backdrop of DNA replication: lessons from genetics and genome-scale analyses. Biochim. Biophys. Acta 1819, 794–801 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Huang, L. et al. Prevention of transcriptional silencing by a replicator-binding complex consisting of SWI/SNF, MeCP1 and hnRNP C1/C2. Mol. Cell. Biol. 31, 3472–3484 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Majocchi, S., Aritonovska, E. & Mermod, N. Epigenetic regulatory elements associate with specific histone modifications to prevent silencing of telomeric genes. Nucleic Acids Res. 42, 193–204 (2014).

    CAS  PubMed  Google Scholar 

  56. Muller-Kuller, U. et al. A minimal ubiquitous chromatin opening element (UCOE) effectively prevents silencing of juxtaposed heterologous promoters by epigenetic remodeling in multipotent and pluripotent stem cells. Nucleic Acids Res. 43, 1577–1592 (2015).

    PubMed  PubMed Central  Google Scholar 

  57. Smith, O. K. & Aladjem, M. I. Chromatin structure and replication origins: determinants of chromosome replication and nuclear organization. J. Mol. Biol. 426, 3330–3341 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Fu, H. et al. Methylation of histone H3 on lysine 79 associates with a group of replication origins and helps limit DNA replication once per cell cycle. PLoS Genet. 9, e1003542 (2013). This was the first report of a histone modification that specifically marks replication origins and functions to prevent re-replication in mammalian cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Karnani, N., Taylor, C. M., Malhotra, A. & Dutta, A. 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 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Feng, Y. et al. BRPF3–HBO1 regulates replication origin activation and histone H3K14 acetylation. EMBO J. 35, 176–192 (2016).

    CAS  PubMed  Google Scholar 

  61. Goldar, A. et al. Deciphering DNA replication dynamics in eukaryotic cell populations in relation with their averaged chromatin conformations. Sci. Rep. 6, 22469 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Picard, F. et al. The spatiotemporal program of DNA replication is associated with specific combinations of chromatin marks in human cells. PLoS Genet. 10, e1004282 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. Lubelsky, Y. et al. DNA replication and transcription programs respond to the same chromatin cues. Genome Res. 24, 1102–1114 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Tardat, M. et al. The histone H4 lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells. Nat. Cell Biol. 12, 1086–1093 (2010).

    CAS  PubMed  Google Scholar 

  65. Kuo, A. J. et al. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier–Gorlin syndrome. Nature 484, 115–119 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Iizuka, M., Matsui, T., Takisawa, H. & Smith, M. M. Regulation of replication licensing by acetyltransferase Hbo1. Mol. Cell. Biol. 26, 1098–1108 (2006). References 64, 65, 66 demonstrate that the initiation of DNA replication requires a chromatin modification, methylation of histone H4 on lysine 20, which is recognized by the ORC1 component of the pre-replication complex.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. McConnell, K. H., Dixon, M. & Calvi, B. R. The histone acetyltransferases CBP and Chameau integrate developmental and DNA replication programs in Drosophila ovarian follicle cells. Development 139, 3880–3890 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, Y., Armstrong, R. L., Duronio, R. J. & MacAlpine, D. M. Methylation of histone H4 lysine 20 by PR-Set7 ensures the integrity of late replicating sequence domains in Drosophila. Nucleic Acids Res. 44, 7204–7218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Stroud, H. et al. DNA methyltransferases are required to induce heterochromatic re-replication in Arabidopsis. PLoS Genet. 8, e1002808 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Aladjem, M. I. et al. Participation of the human β-globin locus control region in initiation of DNA replication. Science 270, 815–819 (1995).

    CAS  PubMed  Google Scholar 

  71. Kalejta, R. F. et al. Distal sequences, but not ori-β/OBR-1, are essential for initiation of DNA replication in the Chinese hamster DHFR origin. Mol. Cell 2, 797–806 (1998).

    CAS  PubMed  Google Scholar 

  72. Hayashida, T. et al. Replication initiation from a novel origin identified in the Th2 cytokine cluster locus requires a distant conserved noncoding sequence. J. Immunol. 176, 5446–5454 (2006).

    CAS  PubMed  Google Scholar 

  73. Guillou, E. et al. Cohesin organizes chromatin loops at DNA replication factories. Genes Dev. 24, 2812–2822 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Foti, R. et al. Nuclear architecture organized by Rif1 underpins the replication-timing program. Mol. Cell 61, 260–273 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Hiraga, S. et al. Rif1 controls DNA replication by directing protein phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex. Genes Dev. 28, 372–383 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Hoggard, T., Shor, E., Muller, C. A., Nieduszynski, C. A. & Fox, C. A. A link between ORC-origin binding mechanisms and origin activation time revealed in budding yeast. PLoS Genet. 9, e1003798 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Nieduszynski, C. A., Blow, J. J. & Donaldson, A. D. The requirement of yeast replication origins for pre-replication complex proteins is modulated by transcription. Nucleic Acids Res. 33, 2410–2420 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. DePamphilis, M. L. et al. Regulating the licensing of DNA replication origins in metazoa. Curr. Opin. Cell Biol. 18, 231–239 (2006).

    CAS  PubMed  Google Scholar 

  79. Hiratani, I. et al. Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis. Genome Res. 20, 155–169 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Anglana, M., Apiou, F., Bensimon, A. & Debatisse, M. Dynamics of DNA replication in mammalian somatic cells: nucleotide pool modulates origin choice and interorigin spacing. Cell 114, 385–394 (2003). This study showed that the locations of replication origins are flexible and can be altered by metabolic conditions.

    CAS  PubMed  Google Scholar 

  81. Debatisse, M., Le Tallec, B., Letessier, A., Dutrillaux, B. & Brison, O. Common fragile sites: mechanisms of instability revisited. Trends Genet. 28, 22–32 (2012).

    CAS  PubMed  Google Scholar 

  82. Gerhardt, J. et al. The DNA replication program is altered at the FMR1 locus in fragile X embryonic stem cells. Mol. Cell 53, 19–31 (2014). The study showed that changes in replication origin usage are associated with replication fork stalling and repeat instability, which lead to repeat expansion at the FMR1 locus during early embryogenesis.

    CAS  PubMed  Google Scholar 

  83. Fu, H. et al. The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage. Nat. Commun. 6, 6746 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Ozeri-Galai, E., Tur-Sinai, M., Bester, A. C. & Kerem, B. Interplay between genetic and epigenetic factors governs common fragile site instability in cancer. Cell. Mol. Life Sci. 71, 4495–4506 (2014).

    CAS  PubMed  Google Scholar 

  85. Bielinsky, A. K. Replication origins: why do we need so many? Cell Cycle 2, 307–309 (2003).

    CAS  PubMed  Google Scholar 

  86. Blow, J. J., Ge, X. Q. & Jackson, D. A. How dormant origins promote complete genome replication. Trends Biochem. Sci. 36, 405–414 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Conti, C. et al. Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage. Cancer Res. 70, 4470–4480 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen, Y. H. et al. ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. Mol. Cell 58, 323–338 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Regairaz, M. et al. Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I–DNA complexes. J. Cell Biol. 195, 739–749 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. DePamphilis, M. L. Replication origins in metazoan chromosomes: fact or fiction? Bioessays 21, 5–16 (1999).

    CAS  PubMed  Google Scholar 

  91. Donley, N., Smith, L. & Thayer, M. J. ASAR15, a cis-acting locus that controls chromosome-wide replication timing and stability of human chromosome 15. PLoS Genet. 11, e1004923 (2015).

    PubMed  PubMed Central  Google Scholar 

  92. Flickinger, R. A. Possible role of H1 histone in replication timing. Dev. Growth Differ. 57, 1–9 (2015).

    CAS  PubMed  Google Scholar 

  93. Schepers, A. & Papior, P. Why are we where we are? Understanding replication origins and initiation sites in eukaryotes using ChIP-approaches. Chromosome Res. 18, 63–77 (2010).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  95. Knott, S. R. et al. Forkhead transcription factors establish origin timing and long-range clustering in S. cerevisiae. Cell 148, 99–111 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Peace, J. M., Villwock, S. K., Zeytounian, J. L., Gan, Y. & Aparicio, O. M. Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase. Genome Res. 26, 365–375 (2016). References 95 and 96 report a specific interaction between yeast transcription factors and replication origins that modulates the timing of replication by facilitating clustering of early-replicating origins with pre-replication complex proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Donti, T. R., Datta, S., Sandoval, P. Y. & Kapler, G. M. Differential targeting of Tetrahymena ORC to ribosomal DNA and non-rDNA replication origins. EMBO J. 28, 223–233 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Chiang, C. M. et al. Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins. Proc. Natl Acad. Sci. USA 89, 5799–5803 (1992).

    CAS  PubMed  Google Scholar 

  99. Schepers, A. et al. Human origin recognition complex binds to the region of the latent origin of DNA replication of Epstein–Barr virus. EMBO J. 20, 4588–4602 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Sears, J., Kolman, J., Wahl, G. M. & Aiyar, A. Metaphase chromosome tethering is necessary for the DNA synthesis and maintenance of oriP plasmids but is insufficient for transcription activation by Epstein–Barr nuclear antigen 1. J. Virol. 77, 11767–11780 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Piirsoo, M., Ustav, E., Mandel, T., Stenlund, A. & Ustav, M. Cis and trans requirements for stable episomal maintenance of the BPV-1 replicator. EMBO J. 15, 1–11 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. McPhillips, M. G., Oliveira, J. G., Spindler, J. E., Mitra, R. & McBride, A. A. Brd4 is required for E2-mediated transcriptional activation but not genome partitioning of all papillomaviruses. J. Virol. 80, 9530–9543 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. McPhillips, M. G., Ozato, K. & McBride, A. A. Interaction of bovine papillomavirus E2 protein with Brd4 stabilizes its association with chromatin. J. Virol. 79, 8920–8932 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Parish, J. L., Bean, A. M., Park, R. B. & Androphy, E. J. ChlR1 is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance. Mol. Cell 24, 867–876 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  106. Beall, E. L. et al. Role for a Drosophila Myb-containing protein complex in site-specific DNA replication. Nature 420, 833–837 (2002).

    CAS  PubMed  Google Scholar 

  107. Aggarwal, B. D. & Calvi, B. R. Chromatin regulates origin activity in Drosophila follicle cells. Nature 430, 372–376 (2004).

    CAS  PubMed  Google Scholar 

  108. Ghosh, M. et al. Differential binding of replication proteins across the human c-myc replicator. Mol. Cell. Biol. 26, 5270–5283 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Chowdhury, A. et al. The DNA unwinding element binding protein DUE-B interacts with Cdc45 in preinitiation complex formation. Mol. Cell. Biol. 30, 1495–1507 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Thangavel, S. et al. Human RECQ1 and RECQ4 helicases play distinct roles in DNA replication initiation. Mol. Cell. Biol. 30, 1382–1396 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Im, J. S. et al. RecQL4 is required for the association of Mcm10 and Ctf4 with replication origins in human cells. Cell Cycle 14, 1001–1009 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Miotto, B. & Struhl, K. HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1. Genes Dev. 22, 2633–2638 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Miotto, B. & Struhl, K. HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by geminin. Mol. Cell 37, 57–66 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Miotto, B. & Struhl, K. JNK1 phosphorylation of Cdt1 inhibits recruitment of HBO1 histone acetylase and blocks replication licensing in response to stress. Mol. Cell 44, 62–71 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhang, Y. et al. A replicator-specific binding protein essential for site-specific initiation of DNA replication in mammalian cells. Nat. Commun. 7, 11748 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Mahajan, M. C., Karmakar, S. & Weissman, S. M. Control of beta globin genes. J. Cell. Biochem. 102, 801–810 (2007).

    CAS  PubMed  Google Scholar 

  117. Sugimoto, N. et al. Cdt1-binding protein GRWD1 is a novel histone-binding protein that facilitates MCM loading through its influence on chromatin architecture. Nucleic Acids Res. 43, 5898–5911 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Jin, J., Arias, E. E., Chen, J., Harper, J. W. & Walter, J. C. A family of diverse Cul4–Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol. Cell 23, 709–721 (2006).

    CAS  PubMed  Google Scholar 

  119. Higa, L. A. et al. CUL4–DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat. Cell Biol. 8, 1277–1283 (2006).

    CAS  PubMed  Google Scholar 

  120. Comelli, L. et al. The homeotic protein HOXC13 is a member of human DNA replication complexes. Cell Cycle 8, 454–459 (2009).

    CAS  PubMed  Google Scholar 

  121. Salsi, V. et al. HOXD13 binds DNA replication origins to promote origin licensing and is inhibited by geminin. Mol. Cell. Biol. 29, 5775–5788 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Budhavarapu, V. N., Chavez, M. & Tyler, J. K. How is epigenetic information maintained through DNA replication? Epigenetics Chromatin 6, 32 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Demczuk, A. et al. Regulation of DNA replication within the immunoglobulin heavy-chain locus during B cell commitment. PLoS Biol. 10, e1001360 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Koren, A. et al. Genetic variation in human DNA replication timing. Cell 159, 1015–1026 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Mukhopadhyay, R. et al. Allele-specific genome-wide profiling in human primary erythroblasts reveal replication program organization. PLoS Genet. 10, e1004319 (2014). References 124 and 125 show that variations in replication timing can be associated with specific alleles, suggesting a role for cis -acting elements in the determination of replication timing.

    PubMed  PubMed Central  Google Scholar 

  126. Li, P. C., Chretien, L., Cote, J., Kelly, T. J. & Forsburg, S. L. S. pombe replication protein Cdc18 (Cdc6) interacts with Swi6 (HP1) heterochromatin protein: region specific effects and replication timing in the centromere. Cell Cycle. 10, 323–336 (2011).

    PubMed  PubMed Central  Google Scholar 

  127. Hayashi, M. T., Takahashi, T. S., Nakagawa, T., Nakayama, J. & Masukata, H. The heterochromatin protein Swi6/HP1 activates replication origins at the pericentromeric region and silent mating-type locus. Nat. Cell Biol. 11, 357–362 (2009).

    CAS  PubMed  Google Scholar 

  128. Tazumi, A. et al. Telomere-binding protein Taz1 controls global replication timing through its localization near late replication origins in fission yeast. Genes Dev. 26, 2050–2062 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Zofall, M., Smith, D. R., Mizuguchi, T., Dhakshnamoorthy, J. & Grewal, S. I. Taz1–shelterin promotes facultative heterochromatin assembly at chromosome-internal sites containing late replication origins. Mol. Cell 62, 862–874 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Tashiro, S. et al. Shugoshin forms a specialized chromatin domain at subtelomeres that regulates transcription and replication timing. Nat. Commun. 7, 10393 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Schwaiger, M., Kohler, H., Oakeley, E. J., Stadler, M. B. & Schubeler, D. Heterochromatin protein 1 (HP1) modulates replication timing of the Drosophila genome. Genome Res. 20, 771–780 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Giri, S. et al. The preRC protein ORCA organizes heterochromatin by assembling histone H3 lysine 9 methyltransferases on chromatin. eLife 4, e06496 (2015).

    PubMed Central  Google Scholar 

  133. Yamazaki, S. et al. Rif1 regulates the replication timing domains on the human genome. EMBO J. 31, 3667–3677 (2012). References 74, 75 and 133 identify the RIF1 protein as a determinant of replication timing in mammalian cells and propose that it modulates the activity of the MCM replicative helicase by interfering with an essential phosphorylation step.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Koren, A. & McCarroll, S. A. Random replication of the inactive X chromosome. Genome Res. 24, 64–69 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Kenigsberg, E. et al. The mutation spectrum in genomic late replication domains shapes mammalian GC content. Nucleic Acids Res. 44, 4222–4232 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. De, S. & Michor, F. DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. Nat. Biotechnol. 29, 1103–1108 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Ryba, T. et al. Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res. 20, 761–770 (2011).

    Google Scholar 

  138. Hiratani, I., Takebayashi, S., Lu, J. & Gilbert, D. M. Replication timing and transcriptional control: beyond cause and effect — part II. Curr. Opin. Genet. Dev. 19, 142–149 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Yaffe, E. et al. Comparative analysis of DNA replication timing reveals conserved large-scale chromosomal architecture. PLoS Genet. 6, e1001011 (2010).

    PubMed  PubMed Central  Google Scholar 

  140. Thayer, M. J. Mammalian chromosomes contain cis-acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes. Bioessays 34, 760–770 (2012). This essay describes studies showing that cis -acting elements can regulate the replication timing of entire chromosomes in cancer cells and thus affect genomic stability.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Mendez, J. Temporal regulation of DNA replication in mammalian cells. Crit. Rev. Biochem. Mol. Biol. 44, 343–351 (2009).

    CAS  PubMed  Google Scholar 

  142. Wu, J. R. & Gilbert, D. M. A distinct G1 step required to specify the Chinese hamster DHFR replication origin. Science 271, 1270–1272 (1996).

    CAS  PubMed  Google Scholar 

  143. Mantiero, D., Mackenzie, A., Donaldson, A. & Zegerman, P. Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast. EMBO J. 30, 4805–4814 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Tanaka, S., Nakato, R., Katou, Y., Shirahige, K. & Araki, H. Origin association of Sld3, Sld7, and Cdc45 proteins is a key step for determination of origin-firing timing. Curr. Biol. 21, 2055–2063 (2011).

    CAS  PubMed  Google Scholar 

  145. Bustin, M. & Misteli, T. Nongenetic functions of the genome. Science 352, aad6933 (2016).

    PubMed  PubMed Central  Google Scholar 

  146. Norio, P. et al. Progressive activation of DNA replication initiation in large domains of the immunoglobulin heavy chain locus during B cell development. Mol. Cell 20, 575–587 (2005). This study directly visualized replication initiation events on stretched DNA fibres, demonstrating that the gradual activation of replication origins correlates with increased replication time during differentiation.

    CAS  PubMed  Google Scholar 

  147. Kawabata, T. et al. Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression. Mol. Cell 41, 543–553 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Luebben, S. W., Kawabata, T., Johnson, C. S., O'Sullivan, M. G. & Shima, N. A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression. Nucleic Acids Res. 42, 5605–5615 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Shirahige, K. et al. Regulation of DNA-replication origins during cell-cycle progression. Nature 395, 618–621 (1998). This was the first report of a cell-cycle checkpoint that regulates the initiation of DNA replication in response to DNA damage.

    CAS  PubMed  Google Scholar 

  150. Seiler, J. A., Conti, C., Syed, A., Aladjem, M. I. & Pommier, Y. The intra-S-phase checkpoint affects both DNA replication initiation and elongation: single-cell and -DNA fiber analyses. Mol. Cell. Biol. 27, 5806–5818 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Naim, V., Wilhelm, T., Debatisse, M. & Rosselli, F. ERCC1 and MUS81–EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nat. Cell Biol. 15, 1008–1015 (2013).

    CAS  PubMed  Google Scholar 

  152. Tuduri, S. et al. Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nat. Cell Biol. 11, 1315–1324 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Courbet, S. et al. Replication fork movement sets chromatin loop size and origin choice in mammalian cells. Nature 455, 557–560 (2008).

    CAS  PubMed  Google Scholar 

  154. Ge, X. Q., Jackson, D. A. & Blow, J. J. Dormant origins licensed by excess Mcm2–7 are required for human cells to survive replicative stress. Genes Dev. 21, 3331–3341 (2007). This study showed that activation of excess dormant origins requires additional MCM helicase complexes and provides the first protection against deleterious replication fork stalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Gerhardt, J. et al. Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation. J. Cell Biol. 206, 599–607 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Dershowitz, A. et al. Linear derivatives of Saccharomyces cerevisiae chromosome III can be maintained in the absence of autonomously replicating sequence elements. Mol. Cell. Biol. 27, 4652–4663 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Shimada, K., Pasero, P. & Gasser, S. M. ORC and the intra-S-phase checkpoint: a threshold regulates Rad53p activation in S phase. Genes Dev. 16, 3236–3252 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Letessier, A. et al. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470, 120–123 (2011).

    CAS  PubMed  Google Scholar 

  159. Casper, A. M., Nghiem, P., Arlt, M. F. & Glover, T. W. ATR regulates fragile site stability. Cell 111, 779–789 (2002).

    CAS  PubMed  Google Scholar 

  160. Franchitto, A. & Pichierri, P. Replication fork recovery and regulation of common fragile sites stability. Cell. Mol. Life Sci. 71, 4507–4517 (2014).

    CAS  PubMed  Google Scholar 

  161. Koundrioukoff, S. et al. Stepwise activation of the ATR signaling pathway upon increasing replication stress impacts fragile site integrity. PLoS Genet. 9, e1003643 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Barlow, J. H. et al. Identification of early replicating fragile sites that contribute to genome instability. Cell 152, 620–632 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

    CAS  PubMed  Google Scholar 

  164. Bicknell, L. S. et al. Mutations in the pre-replication complex cause Meier–Gorlin syndrome. Nat. Genet. 43, 356–359 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Dominguez-Sola, D. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445–451 (2007).

    CAS  PubMed  Google Scholar 

  166. Jones, R. M. et al. Increased replication initiation and conflicts with transcription underlie cyclin E-induced replication stress. Oncogene 32, 3744–3753 (2013).

    CAS  PubMed  Google Scholar 

  167. Vaziri, C. et al. A p53-dependent checkpoint pathway prevents rereplication. Mol. Cell 11, 997–1008 (2003).

    CAS  PubMed  Google Scholar 

  168. Miron, K., Golan-Lev, T., Dvir, R., Ben-David, E. & Kerem, B. Oncogenes create a unique landscape of fragile sites. Nat. Commun. 6, 7094 (2015).

    CAS  PubMed  Google Scholar 

  169. Sheu, Y. J., Kinney, J. B. & Stillman, B. Concerted activities of Mcm4, Sld3, and Dbf4 in control of origin activation and DNA replication fork progression. Genome Res. 26, 315–330 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Aparicio, T., Ibarra, A. & Mendez, J. Cdc45–MCM–GINS, a new power player for DNA replication. Cell Div. 1, 18 (2006).

    PubMed  PubMed Central  Google Scholar 

  171. Depamphilis, M. L., de Renty, C. M., Ullah, Z. & Lee, C. Y. “The Octet”: eight protein kinases that control mammalian DNA replication. Front. Physiol. 3, 368 (2012).

    PubMed  PubMed Central  Google Scholar 

  172. Tanaka, S. & Araki, H. Helicase activation and establishment of replication forks at chromosomal origins of replication. Cold Spring Harb. Perspect. Biol. 5, a010371 (2013).

    PubMed  PubMed Central  Google Scholar 

  173. Sansam, C. G., Goins, D., Siefert, J. C., Clowdus, E. A. & Sansam, C. L. Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation. Genes Dev. 29, 555–566 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Boos, D., Yekezare, M. & Diffley, J. F. Identification of a heteromeric complex that promotes DNA replication origin firing in human cells. Science 340, 981–984 (2013).

    CAS  PubMed  Google Scholar 

  175. Novac, O., Matheos, D., Araujo, F. D., Price, G. B. & Zannis-Hadjopoulos, M. In vivo association of Ku with mammalian origins of DNA replication. Mol. Biol. Cell 12, 3386–3401 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Gao, Y. et al. Protein phosphatase 2A and Cdc7 kinase regulate the DNA unwinding element-binding protein in replication initiation. J. Biol. Chem. 289, 35987–36000 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Sincennes, M. C. et al. The LMO2 oncogene regulates DNA replication in hematopoietic cells. Proc. Natl Acad. Sci. USA 113, 1393–1398 (2016).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank H. Fu, K. Utani, S. Jang, J. Murai, F. E. Indig and A. B. Marks for critical reading of the manuscript, and would like to apologize to colleagues whose primary work could not be cited directly owing to space limitations. Work in the authors' laboratory is funded by the intramural programme of the Centre for Cancer Research, National Cancer Institute, US National Institutes of Health.

Author information

Authors and Affiliations

  1. Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bethesda, 20892, Maryland, USA

    Mirit I. Aladjem & Christophe E. Redon

Authors
  1. Mirit I. Aladjem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christophe E. Redon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mirit I. Aladjem.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Replication origins

Locations on chromatin from which replication forks emanate.

Replicons

Units of chromatin that are replicated from a single origin.

Replication-timing domain

A region on chromatin that exhibits a uniform replication time from multiple adjacent replicons.

Topologically associated domains

Discrete units of chromatin that tend to exhibit internal, rather than external, chromatin interactions that probably reflect distinct folding patterns.

Single-fibre analyses

Studies of chromosomal dynamics that are based on visualization of labelled, stretched single DNA molecules (for example, on microscope slides). Single-fibre replication analyses visualize the incorporation of nucleotide analogues into chromatin fibres.

Replicon model

A model proposing that replication initiates through an interaction between cis-acting elements (replicators) and trans-acting factors (initiators).

Replicators

Genetic elements that are required for the initiation of DNA replication from a particular chromosomal site.

Initiators

Proteins, or protein complexes, that interact with a replicator and are required for initiation of DNA replication.

CpG islands

Stretches of nucleotides (longer than 200 bp) that exhibit a high abundance of CpG dinucleotides.

G-quadruplex structures

Stacked, planar structures formed by intramolecular interactions among DNA sequences that contain multiple stretches of four guanines.

DNA triplexes

Non-B helix-type structures that contain a third strand.

Phased genomes

Assembled genome sequences that identify alleles of maternal and paternal chromosomes.

Negative selection

An evolutionary process by which genetic elements with potentially deleterious effects are removed from a population.

Constitutive origins

DNA replication origins that initiate replication in all cells.

Flexible origins

DNA replication origins that initiate replication in some cells but not in all cells.

Dormant origins

DNA replication origins that undergo replication licensing but do not initiate replication during a typical, unperturbed cell cycle.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aladjem, M., Redon, C. Order from clutter: selective interactions at mammalian replication origins. Nat Rev Genet 18, 101–116 (2017). https://doi.org/10.1038/nrg.2016.141

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg.2016.141

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing