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:

Transcription-replication encounters, consequences and genomic instability

Subjects

Abstract

To ensure accurate duplication of genetic material, the replication fork must overcome numerous natural obstacles on its way, including transcription complexes engaged along the same template. Here we review the various levels of interdependence between transcription and replication processes and how different types of encounters between RNA- and DNA-polymerase complexes may result in clashes of those machineries on the DNA template and thus increase genomic instability. In addition, we summarize strategies evolved in bacteria and eukaryotes to minimize the consequences of collisions, including R-loop formation and topological stresses.

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

Access options

Buy this article

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

Figure 1: Directionality makes the difference.
Figure 2: Consequences of transcription-replication encounters.
Figure 3: Stepwise passage through a collision course.

Similar content being viewed by others

References

  1. Bedinger, P., Hochstrasser, M., Jongeneel, C.V. & Alberts, B.M. Properties of the T4 bacteriophage DNA replication apparatus: the T4 dda DNA helicase is required to pass a bound RNA polymerase molecule. Cell 34, 115–123 (1983).

    Article  CAS  PubMed  Google Scholar 

  2. Breier, A.M., Weier, H.U. & Cozzarelli, N.R. Independence of replisomes in Escherichia coli chromosomal replication. Proc. Natl. Acad. Sci. USA 102, 3942–3947 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mok, M. & Marians, K.J. The Escherichia coli preprimosome and DNA B helicase can form replication forks that move at the same rate. J. Biol. Chem. 262, 16644–16654 (1987).

    CAS  PubMed  Google Scholar 

  4. Epshtein, V., Toulme, F., Rahmouni, A.R., Borukhov, S. & Nudler, E. Transcription through the roadblocks: the role of RNA polymerase cooperation. EMBO J. 22, 4719–4727 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Proshkin, S., Rahmouni, A.R., Mironov, A. & Nudler, E. Cooperation between translating ribosomes and RNA polymerase in transcription elongation. Science 328, 504–508 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. French, S. Consequences of replication fork movement through transcription units in vivo. Science 258, 1362–1365 (1992). This is the first in vivo study of transcription-replication encounters, showing that RNA polymerases are dislodged from a bacterial rRNA operon when a replication fork passes from either the same or the opposite direction.

    Article  CAS  PubMed  Google Scholar 

  7. McGlynn, P., Savery, N.J. & Dillingham, M.S. The conflict between DNA replication and transcription. Mol. Microbiol. 85, 12–20 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Dutta, D., Shatalin, K., Epshtein, V., Gottesman, M.E. & Nudler, E. Linking RNA polymerase backtracking to genome instability in E. coli. Cell 146, 533–543 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Klevecz, R.R., Bolen, J., Forrest, G. & Murray, D.B. A genomewide oscillation in transcription gates DNA replication and cell cycle. Proc. Natl. Acad. Sci. USA 101, 1200–1205 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Reinke, H. & Gatfield, D. Genome-wide oscillation of transcription in yeast. Trends Biochem. Sci. 31, 189–191 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Cho, R.J. et al. A genome-wide transcriptional analysis of the mitotic cell cycle. Mol. Cell 2, 65–73 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Wansink, D.G. et al. RNA polymerase II transcription is concentrated outside replication domains throughout S-phase. J. Cell Sci. 107, 1449–1456 (1994).

    CAS  PubMed  Google Scholar 

  13. Wei, X. et al. Segregation of transcription and replication sites into higher order domains. Science 281, 1502–1506 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Hiratani, I. et al. Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol. 6, e245 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Darzacq, X. et al. In vivo dynamics of RNA polymerase II transcription. Nat. Struct. Mol. Biol. 14, 796–806 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pérez -Ortin, J.E., Alepuz, P.M. & Moreno, J. Genomics and gene transcription kinetics in yeast. Trends Genet. 23, 250–257 (2007).

    Article  PubMed  CAS  Google Scholar 

  17. Singh, J. & Padgett, R.A. Rates of in situ transcription and splicing in large human genes. Nat. Struct. Mol. Biol. 16, 1128–1133 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Azvolinsky, A., Giresi, P.G., Lieb, J.D. & Zakian, V.A. Highly transcribed RNA polymerase II genes are impediments to replication fork progression in Saccharomyces cerevisiae. Mol. Cell 34, 722–734 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Helmrich, A., Ballarino, M. & Tora, L. Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol. Cell 44, 966–977 (2011). This is the first report of naturally occurring collisions in human cells; the authors show that transcription of very long genes takes more than one cell cycle to be completed, and the instability of common fragile sites within those genes is linked to a spatial and temporal overlap between transcription and replication.

    Article  CAS  PubMed  Google Scholar 

  21. Srivatsan, A., Tehranchi, A., MacAlpine, D.M. & Wang, J.D. Co-orientation of replication and transcription preserves genome integrity. PLoS Genet. 6, e1000810 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kunst, F. et al. The complete genome sequence of the gram-positive bacterium Bacillus subtilis. Nature 390, 249–256 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Brewer, B.J. When polymerases collide: replication and the transcriptional organization of the E. coli chromosome. Cell 53, 679–686 (1988).

    Article  CAS  PubMed  Google Scholar 

  24. Deshpande, A.M. & Newlon, C.S. DNA replication fork pause sites dependent on transcription. Science 272, 1030–1033 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. López-Estraño, C., Schvartzman, J.B., Krimer, D.B. & Hernandez, P. Characterization of the pea rDNA replication fork barrier: putative cis-acting and trans-acting factors. Plant Mol. Biol. 40, 99–110 (1999).

    Article  PubMed  Google Scholar 

  26. Maric, C., Levacher, B. & Hyrien, O. Developmental regulation of replication fork pausing in Xenopus laevis ribosomal RNA genes. J. Mol. Biol. 291, 775–788 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, Z., Macalpine, D.M. & Kapler, G.M. Developmental regulation of DNA replication: replication fork barriers and programmed gene amplification in Tetrahymena thermophila. Mol. Cell Biol. 17, 6147–6156 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. López-Estraño, C., Schvartzman, J.B., Krimer, D.B. & Hernandez, P. Co-localization of polar replication fork barriers and rRNA transcription terminators in mouse rDNA. J. Mol. Biol. 277, 249–256 (1998).

    Article  PubMed  Google Scholar 

  29. Putter, V. & Grummt, F. Transcription termination factor TTF-I exhibits contrahelicase activity during DNA replication. EMBO Rep. 3, 147–152 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schübeler, D. et al. Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing. Nat. Genet. 32, 438–442 (2002).

    Article  PubMed  CAS  Google Scholar 

  32. White, E.J. et al. DNA replication-timing analysis of human chromosome 22 at high resolution and different developmental states. Proc. Natl. Acad. Sci. USA 101, 17771–17776 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Woodfine, K. et al. Replication timing of the human genome. Hum. Mol. Genet. 13, 191–202 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. van der Meijden, C.M. et al. Gene profiling of cell cycle progression through S-phase reveals sequential expression of genes required for DNA replication and nucleosome assembly. Cancer Res. 62, 3233–3243 (2002).

    CAS  PubMed  Google Scholar 

  35. Holmes, W.F. et al. Coordinate control and selective expression of the full complement of replication-dependent histone H4 genes in normal and cancer cells. J. Biol. Chem. 280, 37400–37407 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Coffman, F.D., He, M., Diaz, M.L. & Cohen, S. DNA replication initiates at different sites in early and late S phase within human ribosomal RNA genes. Cell Cycle 4, 1223–1226 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Dimitrova, D.S. DNA replication initiation patterns and spatial dynamics of the human ribosomal RNA gene loci. J. Cell Sci. 124, 2743–2752 (2011). This study shows that on active rDNA loci, replication initiates randomly throughout the early-replicating rDNA, whereas silent rDNA replicates inside the nucleoli during mid and late S phase, which ensures efficient replication and reduces the risk of chromosome breaks and rDNA hyper-recombination.

    Article  CAS  PubMed  Google Scholar 

  38. Cadoret, J.C. et al. Genome-wide studies highlight indirect links between human replication origins and gene regulation. Proc. Natl. Acad. Sci. USA 105, 15837–15842 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cayrou, C. et al. Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features. Genome Res. 21, 1438–1449 (2011). By performing a genome-scale purification of DNA replication origins, the authors show that replication-initiation events are most frequent at CpG island–containing promoters in mice and at CpG island–like regions in Drosophila.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chang, V.K., Donato, J.J., Chan, C.S. & Tye, B.K. Mcm1 promotes replication initiation by binding specific elements at replication origins. Mol. Cell Biol. 24, 6514–6524 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Danis, E. et al. Specification of a DNA replication origin by a transcription complex. Nat. Cell Biol. 6, 721–730 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Knott, S.R., Viggiani, C.J., Tavare, S. & Aparicio, O.M. 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, 1077–1090 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hyrien, O., Maric, C. & Mechali, M. Transition in specification of embryonic metazoan DNA replication origins. Science 270, 994–997 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Dimitrova, D.S. Nuclear transcription is essential for specification of mammalian replication origins. Genes Cells 11, 829–844 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Mori, S. & Shirahige, K. Perturbation of the activity of replication origin by meiosis-specific transcription. J. Biol. Chem. 282, 4447–4452 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Letessier, A. et al. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470, 120–123 (2011). The authors show that common fragile sites are epigenetically defined loci corresponding to the latest initiation-poor regions to complete replication in a given cell type.

    Article  CAS  PubMed  Google Scholar 

  48. Vieira, K.F. et al. Recruitment of transcription complexes to the β-globin gene locus in vivo and in vitro. J. Biol. Chem. 279, 50350–50357 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Kim, N. & Jinks-Robertson, S. Transcription as a source of genome instability. Nat. Rev. Genet. 13, 204–214 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Merrikh, H., Zhang, Y., Grossman, A.D. & Wang, J.D. Replication-transcription conflicts in bacteria. Nat. Rev. Microbiol. 10, 449–458 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Prado, F. & Aguilera, A. Impairment of replication fork progression mediates RNA polII transcription-associated recombination. EMBO J. 24, 1267–1276 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Takeuchi, Y., Horiuchi, T. & Kobayashi, T. Transcription-dependent recombination and the role of fork collision in yeast rDNA. Genes Dev. 17, 1497–1506 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vilette, D., Ehrlich, S.D. & Michel, B. Transcription-induced deletions in Escherichia coli plasmids. Mol. Microbiol. 17, 493–504 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Zaratiegui, M. et al. RNAi promotes heterochromatic silencing through replication-coupled release of RNA Pol II. Nature 479, 135–138 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bermejo, R. et al. Genome-organizing factors Top2 and Hmo1 prevent chromosome fragility at sites of S phase transcription. Cell 138, 870–884 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. El Hage, A., French, S.L., Beyer, A.L. & Tollervey, D. Loss of Topoisomerase I leads to R-loop–mediated transcriptional blocks during ribosomal RNA synthesis. Genes Dev. 24, 1546–1558 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ivessa, A.S. et al. The Saccharomyces cerevisiae helicase Rrm3p facilitates replication past nonhistone protein-DNA complexes. Mol. Cell 12, 1525–1536 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Tehranchi, A.K. et al. The transcription factor DksA prevents conflicts between DNA replication and transcription machinery. Cell 141, 595–605 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Trautinger, B.W., Jaktaji, R.P., Rusakova, E. & Lloyd, R.G. RNA polymerase modulators and DNA repair activities resolve conflicts between DNA replication and transcription. Mol. Cell 19, 247–258 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Wahba, L., Amon, J.D., Koshland, D. & Vuica-Ross, M. RNase H and multiple RNA biogenesis factors cooperate to prevent RNA:DNA hybrids from generating genome instability. Mol. Cell 44, 978–988 (2011)This study demonstrates that RNA-DNA hybrids naturally occur in wild-type yeast cells, probably owing to transcriptional errors, and are removed by evolutionarily conserved RNase H enzymes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Washburn, R.S. & Gottesman, M.E. Transcription termination maintains chromosome integrity. Proc. Natl. Acad. Sci. USA 108, 792–797 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Wellinger, R.E., Prado, F. & Aguilera, A. Replication fork progression is impaired by transcription in hyperrecombinant yeast cells lacking a functional THO complex. Mol. Cell Biol. 26, 3327–3334 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li, X. & Manley, J.L. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122, 365–378 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Jones, R.M. et al. Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress. Oncogene advance online publication, doi:10.1038/onc.2012.387 (3 September 2012).

    Article  PubMed  CAS  Google Scholar 

  65. Ozeri-Galai, E., Bester, A.C. & Kerem, B. The complex basis underlying common fragile site instability in cancer. Trends Genet. 28, 295–302 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Helmrich, A., Stout-Weider, K., Hermann, K., Schrock, E. & Heiden, T. Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes. Genome Res. 16, 1222–1230 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yu, K., Chedin, F., Hsieh, C.L., Wilson, T.E. & Lieber, M.R. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nat. Immunol. 4, 442–451 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Wang, J.D., Berkmen, M.B. & Grossman, A.D. Genome-wide coorientation of replication and transcription reduces adverse effects on replication in Bacillus subtilis. Proc. Natl. Acad. Sci. USA 104, 5608–5613 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. De Septenville, A.L., Duigou, S., Boubakri, H. & Michel, B. Replication fork reversal after replication-transcription collision. PLoS Genet. 8, e1002622 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nudler, E. RNA polymerase backtracking in gene regulation and genome instability. Cell 149, 1438–1445 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Borukhov, S., Sagitov, V. & Goldfarb, A. Transcript cleavage factors from E. coli. Cell 72, 459–466 (1993).

    Article  CAS  PubMed  Google Scholar 

  72. Toulmé, F. et al. GreA and GreB proteins revive backtracked RNA polymerase in vivo by promoting transcript trimming. EMBO J. 19, 6853–6859 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Park, J.S. & Roberts, J.W. Role of DNA bubble rewinding in enzymatic transcription termination. Proc. Natl. Acad. Sci. USA 103, 4870–4875 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gan, W. et al. R-loop–mediated genomic instability is caused by impairment of replication fork progression. Genes Dev. 25, 2041–2056 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Stirling, P.C. et al. R-loop–mediated genome instability in mRNA cleavage and polyadenylation mutants. Genes Dev. 26, 163–175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Skourti-Stathaki, K., Proudfoot, N.J. & Gromak, N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol. Cell 42, 794–805 (2011). R loops can be key determinants in transcription termination by recruiting human senataxin and Xrn2 at 3′ cleavage poly(A) sites.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mischo, H.E. et al. Yeast Sen1 helicase protects the genome from transcription-associated instability. Mol. Cell 41, 21–32 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lin, Y., Dent, S.Y., Wilson, J.H., Wells, R.D. & Napierala, M. R loops stimulate genetic instability of CTG.CAG repeats. Proc. Natl. Acad. Sci. USA 107, 692–697 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Reddy, K. et al. Determinants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats. Nucleic Acids Res. 39, 1749–1762 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Grabczyk, E., Mancuso, M. & Sammarco, M.C. A persistent RNA.DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro. Nucleic Acids Res. 35, 5351–5359 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Huertas, P. & Aguilera, A. Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol. Cell 12, 711–721 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Bermejo, R. et al. The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores. Cell 146, 233–246 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Westover, K.D., Bushnell, D.A. & Kornberg, R.D. Structural basis of transcription: separation of RNA from DNA by RNA polymerase II. Science 303, 1014–1016 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Reaban, M.E., Lebowitz, J. & Griffin, J.A. Transcription induces the formation of a stable RNA.DNA hybrid in the immunoglobulin α switch region. J. Biol. Chem. 269, 21850–21857 (1994).

    CAS  PubMed  Google Scholar 

  85. Bochkareva, A., Yuzenkova, Y., Tadigotla, V.R. & Zenkin, N. Factor-independent transcription pausing caused by recognition of the RNA-DNA hybrid sequence. EMBO J. 31, 630–639 (2012). The authors show that the recognition of RNA-DNA hybrid sequence by multisubunit RNA polymerases is involved in transcription regulation and may determine the overall rate of transcription elongation.

    Article  CAS  PubMed  Google Scholar 

  86. Kreuzer, K.N. & Brister, J.R. Initiation of bacteriophage T4 DNA replication and replication fork dynamics: a review in the Virology Journal series on bacteriophage T4 and its relatives. Virol. J. 7, 358 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gómez-González, B., Felipe-Abrio, I. & Aguilera, A. The S-phase checkpoint is required to respond to R-loops accumulated in THO mutants. Mol. Cell Biol. 29, 5203–5213 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Bermejo, R., Lai, M.S. & Foiani, M. Preventing replication stress to maintain genome stability: resolving conflicts between replication and transcription. Mol. Cell 45, 710–718 (2012). The authors show that mRNA-export complex (TREX-2 or THO)-dependent coupling of transcription, gene gating and mRNA biogenesis causes aberrant transitions at stalled forks in replication checkpoint–defective cells.

    Article  CAS  PubMed  Google Scholar 

  89. Pomerantz, R.T. & O'Donnell, M. The replisome uses mRNA as a primer after colliding with RNA polymerase. Nature 456, 762–766 (2008). The authors investigate the stability of the E. coli replisome after encounters with a head-on RNA polymerase and discover a new role for the transcription-coupled repair pathway in facilitating replication through arrested transcription complexes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Saeki, H. & Svejstrup, J.Q. Stability, flexibility, and dynamic interactions of colliding RNA polymerase II elongation complexes. Mol. Cell 35, 191–205 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hobson, D.J., Wei, W., Steinmetz, L.M. & Svejstrup, J.Q. RNA polymerase II collision interrupts convergent transcription. Mol. Cell 48, 365–374 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Pomerantz, R.T. & O'Donnell, M. Direct restart of a replication fork stalled by a head-on RNA polymerase. Science 327, 590–592 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Boubakri, H., de Septenville, A.L., Viguera, E. & Michel, B. The helicases DinG, Rep and UvrD cooperate to promote replication across transcription units in vivo. EMBO J. 29, 145–157 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Merrikh, H., Machon, C., Grainger, W.H., Grossman, A.D. & Soultanas, P. Co-directional replication–transcription conflicts lead to replication restart. Nature 470, 554–557 (2011). This study on highly transcribed rRNA genes was the first direct demonstration that in vivo the restart machinery is involved in resolving potentially deleterious encounters due to head-on and codirectional conflict.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yunger, S., Rosenfeld, L., Garini, Y. & Shav-Tal, Y. Single-allele analysis of transcription kinetics in living mammalian cells. Nat. Methods 7, 631–633 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Daube, S.S. & von Hippel, P.H. Functional transcription elongation complexes from synthetic RNA-DNA bubble duplexes. Science 258, 1320–1324 (1992).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to colleagues whose work could only be cited indirectly, owing to space limitations. We thank S. Bour for help with preparing the figures. A.H. and M.B. were supported by fellowships from Fondation pour la Recherche Médicale. E.N. was supported by grants from the US National Institutes of Health (R01 GM058750) and the Biogerontology Research Foundation, UK. This work was supported by funds from Centre Nationale de la Recherche Scientifique (LEA-SkinChroma), Agence Nationale de la Recherche (ANR-09-BLAN-0266 and ANR-09-BLAN-056), Institut National du Cancer (2008-Ubican) and European Community (EPIDICAN) grants to L.T.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Laszlo Tora.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Helmrich, A., Ballarino, M., Nudler, E. et al. Transcription-replication encounters, consequences and genomic instability. Nat Struct Mol Biol 20, 412–418 (2013). https://doi.org/10.1038/nsmb.2543

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.2543

This article is cited by

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