Abstract
The spatial and temporal organization of genome duplication, also referred to as the replication program, is defined by the distribution and the activities of the sites of replication initiation across the genome. Alterations to the replication profile are associated with cell fate changes during development and in pathologies, but the importance of undergoing S phase with distinct and specific programs remains largely unexplored. We have recently addressed this question, focusing on the interplay between the replication program and genome maintenance. In particular, we demonstrated that when cells encounter challenges to DNA synthesis, the organization of DNA replication drives the response to replication stress that is mediated by the ATR/Rad3 checkpoint pathway, thus shaping the pattern of genome instability along the chromosomes. In this review, we present the major findings of our study and discuss how they may bring new perspectives to our understanding of the biological importance of the replication program.
Similar content being viewed by others
References
Ahuja AK, Jodkowska K, Teloni F et al (2016) A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells. Nat Commun 7:10660. https://doi.org/10.1038/ncomms10660
Bentley NJ, Holtzman DA, Flaggs G et al (1996) The Schizosaccharomyces pombe rad3 checkpoint gene. EMBO J 15:6641–6651
Bester AC, Roniger M, Oren YS et al (2011) Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145:435–446. https://doi.org/10.1016/j.cell.2011.03.044
Byun TS, Pacek M, Yee M-C et al (2005) Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev 19:1040–1052. https://doi.org/10.1101/gad.1301205
Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204. https://doi.org/10.1016/j.molcel.2010.09.019
Cornacchia D, Dileep V, Quivy J-P et al (2012) Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells. EMBO J 31:3678–3690. https://doi.org/10.1038/emboj.2012.214
Desprat R, Thierry-Mieg D, Lailler N et al (2009) Predictable dynamic program of timing of DNA replication in human cells. Genome Res 19:2288–2299. https://doi.org/10.1101/gr.094060.109
Di Rienzi SC, Collingwood D, Raghuraman MK, Brewer BJ (2009) Fragile genomic sites are associated with origins of replication. Genome Biol Evol 1:350–363. https://doi.org/10.1093/gbe/evp034
Donley N, Thayer MJ (2013) DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability. Semin Cancer Biol 23:80–89. https://doi.org/10.1016/j.semcancer.2013.01.001
Edwards RJ, Bentley NJ, Carr AM (1999) A Rad3-Rad26 complex responds to DNA damage independently of other checkpoint proteins. Nat Cell Biol 1:393–398. https://doi.org/10.1038/15623
Eykelenboom JK, Harte EC, Canavan L et al (2013) ATR activates the S-M checkpoint during unperturbed growth to ensure sufficient replication prior to mitotic onset. Cell Rep 5:1095–1107. https://doi.org/10.1016/j.celrep.2013.10.027
Feng W, Collingwood D, Boeck ME et al (2006) Genomic mapping of single-stranded DNA in hydroxyurea-challenged yeasts identifies origins of replication. Nat Cell Biol 8:148–155. https://doi.org/10.1038/ncb1358
Gómez-Escoda B, Wu P-YJ (2018) The organization of genome duplication is a critical determinant of the landscape of genome maintenance. Genome Res. https://doi.org/10.1101/gr.224527.117
Gordon JL, Byrne KP, Wolfe KH (2009) Additions, losses, and rearrangements on the evolutionary route from a reconstructed ancestor to the modern Saccharomyces cerevisiae genome. PLoS Genet 5:e1000485. https://doi.org/10.1371/journal.pgen.1000485
Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319:1352–1355. https://doi.org/10.1126/science.1140735
Hayano M, Kanoh Y, Matsumoto S et al (2012) Rif1 is a global regulator of timing of replication origin firing in fission yeast. Genes Dev 26:137–150. https://doi.org/10.1101/gad.178491.111
Hayashi M, Katou Y, Itoh T et al (2007) Genome-wide localization of pre-RC sites and identification of replication origins in fission yeast. EMBO J 26:1327–1339. https://doi.org/10.1038/sj.emboj.7601585
Heichinger C, Penkett CJ, Bähler J, Nurse P (2006) Genome-wide characterization of fission yeast DNA replication origins. EMBO J 25:5171–5179. https://doi.org/10.1038/sj.emboj.7601390
Hills SA, Diffley JFX (2014) DNA replication and oncogene-induced replicative stress. Curr Biol 24:R435–R444. https://doi.org/10.1016/j.cub.2014.04.012
Hiratani I, Ryba T, Itoh M et al (2008) Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol 6:e245. https://doi.org/10.1371/journal.pbio.0060245
Hiratani I, Ryba T, Itoh M et al (2010) Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis. Genome Res 20:155–169. https://doi.org/10.1101/gr.099796.109
Hyrien O, Maric C, Méchali M (1995) Transition in specification of embryonic metazoan DNA replication origins. Science 270:994–997
Kermi C, Furno Lo E, Maiorano D (2017) Regulation of DNA replication in early embryonic cleavages. Genes (Basel). https://doi.org/10.3390/genes8010042
Koren A, Polak P, Nemesh J et al (2012) Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet 91:1033–1040. https://doi.org/10.1016/j.ajhg.2012.10.018
Kotsantis P, Petermann E, Boulton SJ (2018) Mechanisms of oncogene-induced replication stress: jigsaw falling into place. Cancer Discov 8:537–555. https://doi.org/10.1158/2159-8290.CD-17-1461
Labib K, De Piccoli G (2011) Surviving chromosome replication: the many roles of the S-phase checkpoint pathway. Philos Trans R Soc B Biol Sci 366:3554–3561. https://doi.org/10.1098/rstb.2011.0071
Lang GI, Murray AW (2011) Mutation rates across budding yeast chromosome VI are correlated with replication timing. Genome Biol Evol 3:799–811. https://doi.org/10.1093/gbe/evr054
Lindsay HD, Griffiths DJ, Edwards RJ et al (1998) S-phase-specific activation of Cds1 kinase defines a subpathway of the checkpoint response in Schizosaccharomyces pombe. Genes Dev 12:382–395
Liu L, De S, Michor F (2013) DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Nat Commun 4:1502. https://doi.org/10.1038/ncomms2502
Lopez-Mosqueda J, Maas NL, Jonsson ZO et al (2010) Damage-induced phosphorylation of Sld3 is important to block late origin firing. Nature 467:479–483. https://doi.org/10.1038/nature09377
Lu J, Li H, Hu M et al (2014) The distribution of genomic variationsin human iPSCs is related to replication-timing reorganization during reprogramming. Cell Rep 7:70–78. https://doi.org/10.1016/j.celrep.2014.03.007
Mazouzi A, Velimezi G, Loizou JI (2014) DNA replication stress—causes, resolution and disease. Exp Cell Res 329:85–93. https://doi.org/10.1016/j.yexcr.2014.09.030
McGranahan N, Swanton C (2017) Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168:613–628. https://doi.org/10.1016/j.cell.2017.01.018
Mickle KL, Ramanathan S, Rosebrock A et al (2007) Checkpoint independence of most DNA replication origins in fission yeast. BMC Mol Biol 8:112. https://doi.org/10.1186/1471-2199-8-112
Mikolaskova B, Jurcik M, Cipakova I et al (2018) Maintenance of genome stability: the unifying role of interconnections between the DNA damage response and RNA-processing pathways. Curr Genet 64:971–983. https://doi.org/10.1007/s00294-018-0819-7
Misteli T, Soutoglou E (2009) The emerging role of nuclear architecture in DNA repair and genome maintenance. Nature 10:243–254. https://doi.org/10.1038/nrm2651
Muller CA, Nieduszynski CA (2012) Conservation of replication timing reveals global and local regulation of replication origin activity. Genome Res 22:1953–1962. https://doi.org/10.1101/gr.139477.112
Müller CA, Nieduszynski CA (2017) DNA replication timing influences gene expression level. J Cell Biol 216:1907–1914. https://doi.org/10.1083/jcb.201701061
Nagai S, Heun P, Gasser SM (2010) Roles for nuclear organization in the maintenance of genome stability. Epigenomics 2:289–305. https://doi.org/10.2217/epi.09.49
Negrini S, Gorgoulis VG, Halazonetis TD (2010) Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11:220–228. https://doi.org/10.1007/BF01882039
Palou R, Palou G, Quintana DG (2017) A role for the spindle assembly checkpoint in the DNA damage response. Curr Genet 63:275–280. https://doi.org/10.1007/s00294-016-0634-y
Perrot A, Millington CL, Gómez-Escoda B et al (2018) CDK activity provides temporal and quantitative cues for organizing genome duplication. PLoS Genet 14:e1007214. https://doi.org/10.1371/journal.pgen.1007214
Polak P, Karlić R, Koren A et al (2015) Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518:360–364. https://doi.org/10.1038/nature14221
Pope BD, Hiratani I, Gilbert DM (2010) Domain-wide regulation of DNA replication timing during mammalian development. Chromosome Res 18:127–136. https://doi.org/10.1007/s10577-009-9100-8
Pourkarimi E, Bellush JM, Whitehouse I (2016) Spatiotemporal coupling and decoupling of gene transcription with DNA replication origins during embryogenesis in C. elegans. Elife. https://doi.org/10.7554/eLife.21728
Rivera-Mulia JC, Buckley Q, Sasaki T et al (2015) Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells. Genome Res 25:1091–1103. https://doi.org/10.1101/gr.187989.114
Rivera-Mulia JC, Dimond A, Vera D et al (2018) Allele-specific control of replication timing and genome organization during development. Genome Res. https://doi.org/10.1101/gr.232561.117
Rodríguez-Martínez M, Pinzón N, Ghommidh C et al (2017) The gastrula transition reorganizes replication-origin selection in Caenorhabditis elegans. Nat Struct Mol Biol 24:290–299. https://doi.org/10.1038/nsmb.3363
Ryba T, Hiratani I, Lu J et al (2010) Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res 20:761–770. https://doi.org/10.1101/gr.099655.109
Ryba T, Hiratani I, Sasaki T et al (2011) Replication timing: a fingerprint for cell identity and pluripotency. PLoS Comput Biol 7:e1002225. https://doi.org/10.1371/journal.pcbi.1002225
Saldivar JC, Cortez D, Cimprich KA (2017) The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat Rev Mol Cell Biol 18:622–636. https://doi.org/10.1038/nrm.2017.67
Santocanale C, Diffley JF (1998) A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature 395:615–618. https://doi.org/10.1038/27001
Santocanale C, Sharma K, Diffley JF (1999) Activation of dormant origins of DNA replication in budding yeast. Genes Dev 13:2360–2364
Shirahige K, Hori Y, Shiraishi K et al (1998) Regulation of DNA-replication origins during cell-cycle progression. Nature 395:618–621. https://doi.org/10.1038/27007
Sima J, Gilbert DM (2014) Complex correlations: replication timing and mutational landscapes during cancer and genome evolution. Curr Opin Genet Dev 25:93–100. https://doi.org/10.1016/j.gde.2013.11.022
Singh B, Wu P-YJ (2018) Regulation of the program of DNA replication by CDK: new findings and perspectives. Curr Genet. https://doi.org/10.1007/s00294-018-0860-6
Tomkova M, Tomek J, Kriaucionis S, Schuster-Böckler B (2018) Mutational signature distribution varies with DNA replication timing and strand asymmetry. Genome Biol 19:129. https://doi.org/10.1186/s13059-018-1509-y
Tubbs A, Nussenzweig A (2017) Endogenous DNA damage as a source of genomic instability in cancer. Cell 168:644–656. https://doi.org/10.1016/j.cell.2017.01.002
Villa-Hernández S, Bermejo R (2018) Cohesin dynamic association to chromatin and interfacing with replication forks in genome integrity maintenance. Curr Genet 64:1005–1013. https://doi.org/10.1007/s00294-018-0824-x
Willis NA, Zhou C, Elia AEH et al (2016) Identification of S-phase DNA damage-response targets in fission yeast reveals conservation of damage-response networks. Proc Natl Acad Sci USA 113:E3676–E3685. https://doi.org/10.1073/pnas.1525620113
Wu P-YJ, Nurse P (2014) Replication origin selection regulates the distribution of meiotic recombination. Mol Cell 53:655–662. https://doi.org/10.1016/j.molcel.2014.01.022
Yaffe E, Farkash-Amar S, Polten A et al (2010) Comparative analysis of DNA replication timing reveals conserved large-scale chromosomal architecture. PLoS Genet 6:e1001011. https://doi.org/10.1371/journal.pgen.1001011
Yamazaki S, Ishii A, Kanoh Y et al (2012) Rif1 regulates the replication timing domains on the human genome. EMBO J 31:3667–3677. https://doi.org/10.1038/emboj.2012.180
Zegerman P, Diffley JFX (2010) Checkpoint-dependent inhibition of DNA replication initiation by Sld3 and Dbf4 phosphorylation. Nature 467:474–478. https://doi.org/10.1038/nature09373
Zeman MK, Cimprich KA (2014) Causes and consequences of replication stress. Nat Cell Biol 16:2–9. https://doi.org/10.1038/ncb2897
Acknowledgements
We thank Damien Coudreuse for critical reading of the manuscript. This work was supported by funding from the Institut National du Cancer (INCA, PLBIO 15-043) and the Région Bretagne. We apologize to any authors whose work was not cited due to space restrictions.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Communicated by M. Kupiec.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Singh, B., Wu, PY.J. Linking the organization of DNA replication with genome maintenance. Curr Genet 65, 677–683 (2019). https://doi.org/10.1007/s00294-018-0923-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00294-018-0923-8