Abstract
Cells induce the expression of DNA-repair enzymes, activate cell-cycle checkpoints and, under some circumstances, undergo apoptosis in response to DNA-damaging agents. The mechanisms by which these cellular responses are triggered are not well understood, but there is recent evidence that the transcription machinery might be used in DNA-damage surveillance and in triggering DNA-damage responses to suppress mutagenesis. Transcription might also act as a DNA-damage dosimeter where the severity of blockage determines whether or not to induce cell death. Could transcription therefore be a potential therapeutic target for anticancer strategies?
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnrc1435/MediaObjects/41568_2004_Article_BFnrc1435_Fig1_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnrc1435/MediaObjects/41568_2004_Article_BFnrc1435_Fig2_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnrc1435/MediaObjects/41568_2004_Article_BFnrc1435_Fig3_HTML.jpg)
Similar content being viewed by others
References
Mellon, I., Spivak, G. & Hanawalt, P. C. Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Cell 51, 241–249 (1987).
Christians, F. C. & Hanawalt, P. C. Lack of Transcription-coupled repair in mammalian ribosomal RNA genes. Biochemistry 32, 10512–10518 (1993).
Dammann, R. & Pfeifer, G. P. Lack of gene- and strand-specific DNA repair in RNA polymerase III-transcribed human tRNA genes. Mol. Cell. Biol. 17, 219–229 (1997).
Mitchell, J. R., Hoeijmakers, J. H. & Niedernhofer, L. J. Divide and conquer: nucleotide excision repair battles cancer and ageing. Curr. Opin. Cell Biol. 15, 232–240 (2003).
Ljungman, M. & Zhang, F. Blockage of RNA polymerase as a possible trigger for UV light-induced apoptosis. Oncogene 13, 823–831 (1996).
Andera, L. & Wasylyk, B. Transcription abnormalities potentiate apoptosis of normal human fibroblasts. Mol. Med. 3, 852–863 (1997).
Ljungman, M., Zhang, F. F., Chen, F., Rainbow, A. J. & McKay, B. C. Inhibition of RNA polymerase II as a trigger for the p53 response. Oncogene 18, 583–592 (1999).
van Oosten, M. et al. Differential role of transcription-coupled repair in UVB-induced G(2) arrest and apoptosis in mouse epidermis. Proc. Natl Acad. Sci. USA 97, 11268–11273 (2000).
Brash, D. E. et al. The DNA damage signal for Mdm2 regulation, Trp53 induction, and sunburn cell formation in vivo originates from actively transcribed genes. J. Invest. Derm. 117, 1234–1240 (2001).
Queille, S., Drougard, C., Sarasin, A. & Daya-Grosjean, L. Effects of XPD mutations on ultraviolet-induced apoptosis in relation to skin cancer-proneness in repair-deficient syndromes. J. Invest. Derm. 117, 1162–1170 (2001).
McKay, B. C., Becerril, C. & Ljungman, M. P53 plays a protective role against UV- and cisplatin-induced apoptosis in transcription-coupled repair proficient fibroblasts. Oncogene 20, 6805–6808 (2001).
van Gijssel, H. E., Mullenders, L. H., van Oosterwijk, M. F. & Meerman, J. H. Blockage of transcription as a trigger for p53 accumulation by 2-acetylaminofluorene DNA-adducts. Life Sci. 73, 1759–1771 (2003).
Shen, H. et al. Smoking, DNA repair capacity and risk of nonsmall cell lung cancer. Int. J. Cancer 107, 84–88 (2003).
Park, J. Y. et al. Polymorphisms of the DNA repair gene xeroderma pigmentosum group A and risk of primary lung cancer. Cancer Epidemiol. Biomarkers Prev. 11, 993–997 (2002).
Wei, Q. et al. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J. Natl Cancer Inst. 92, 1764–1772 (2000).
Wei, Q. Y., Cheng, L., Hong, W. K. & Spitz, M. R. Reduced DNA repair capacity in lung cancer patients. Cancer Res. 56, 4103–4107 (1996).
Shi, Q. et al. Reduced DNA repair of benzo(a)pyrene diol epoxide-induced adducts and common XPD polymorphisms in breast cancer patients. Carcinogenesis (in the press).
Ramos, J. M. et al. DNA repair and breast carcinoma susceptibility in women. Cancer 100, 1352–1357 (2004).
Lane, D. p53, guardian of the genome. Nature 358, 15–16 (1992).
Ljungman, M. Dial 9-1-1 for p53: Mechanisms of p53 activation by cellular stress. Neoplasia 2, 208–225 (2000).
Yamaizumi, M. & Sugano, T. UV-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle. Oncogene 9, 2775–2784 (1994).
Dumaz, N. et al. Prolonged p53 protein accumulation in trichothiodystrophy fibroblasts dependent on unrepaired pyrimidine dimers on the transcribed strands of cellular genes. Mol. Carcinogen. 20, 340–347 (1997).
McKay, B. C., Ljungman, M. & Rainbow, A. J. Persistent DNA damage induced by ultraviolet light inhibits p21waf1 and bax expression: implications for DNA repair, UV sensitivity and the induction of apoptosis. Oncogene 17, 545–555 (1998).
Blattner, C., Bender, K., Herrlich, P. & Rahmsdorf, H. Photoproducts in transcriptionally active DNA induce signal transduction to delay U. V.-responsive genes for collagenase and metallothionein. Oncogene 16, 2827–2834 (1998).
van Hoffen, A., Balajee, A. S., van Zeeland, A. A. & Mullenders, L. H. Nucleotide excision repair and its interplay with transcription. Toxicology 193, 79–90 (2003).
de Boer, J. et al. Premature aging in mice deficient in DNA repair and transcription. Science 296, 1276–1279 (2002).
de Boer, J. et al. A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy. Mol. Cell 1, 981–990 (1998).
de Boer, J. et al. Mouse model for the DNA repair/basal transcription disorder trichotiodystrophy reveals cancer predisposition. Cancer Res. 59, 3489–3494 (1999).
Garssen, J. et al. Transcription-coupled and global genome repair differentially influence UV-B-induced acute skin effects and systemic immunosuppression. J. Immunol. 164, 6199–6205 (2000).
Ljungman, M., O'Hagan, H. M. & Paulsen, M. T. Induction of ser15 and lys382 modifications of p53 by blockage of transcription elongation. Oncogene 20, 5964–5971 (2001).
Klibanov, S. A., O'Hagan, H. M. & Ljungman, M. Accumulation of soluble and nucleolar-associated p53 proteins following cellular stress. J. Cell Sci. 114, 1867–1873 (2001).
O'Hagan, H. M. & Ljungman, M. Phosphorylation and nuclear accumulation are distinct events contributing to the activation of p53. Mutat. Res. 546, 7–15 (2004).
Lane, D. P. & Hall, P. A. MDM2- arbiter of p53's destruction. Trends Biochem. Sci. 22, 372–374 (1997).
Freedman, D. A. & Levine, A. J. Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol. Cell. Biol. 18, 7288–7293 (1998).
Boyd, S. D., Tsai, K. Y. & Jacks, T. An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nature Cell Biol. 2, 563–568 (2000).
Geyer, R. K., Yu, Z. K. & Maki, C. G. The MDM2 RING-finger domain is required to promote p53 nuclear export. Nature Cell Biol. 2, 569–573 (2000).
Gu, J. J., Nie, L. H., Wiederschain, D. & Yuan, Z. M. Identification of p53 sequence elements that are required for MDM2-mediated nuclear export. Mol. Cell. Biol. 21, 8533–8546 (2001).
Lohrum, M. A. E., Woods, D. B., Ludwig, R. L., Balint, E. & Vousden, K. H. C-terminal ubiquitination of p53 contributes to nuclear export. Mol. Cell. Biol. 21, 8521–8532 (2001).
Blattner, C., Sparks, A. & Lane, D. Transcription factor E2F-1 is upregulated in response to DNA damage in a manner analogous to that of p53. Mol. Cell. Biol. 19, 3704–3713 (1999).
Ashcroft, M., Taya, Y. & Vousden, K. H. Stress signals utilize multiple pathways to stabilize p53. Mol. Cell. Biol. 20, 3224–3233 (2000).
Conforti, G., Nardo, T., D'Incalci, M. & Stefanini, M. Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation. Oncogene 19, 2714–2720 (2000).
Blagosklonny, M., Demidenko, Z. & Fojo, T. Inhibition of transcription results in accumulation of wt p53 followed by delayed outburst of p53-inducible proteins: p53 as a sensor of transcriptional integrity. Cell Cycle 1, 67–74 (2002).
O'Hagan, H. M. & Ljungman, M. Nuclear accumulation of p53 following inhibition of transcription is not due to diminished levels of MDM2. Oncogene 23, 5505–5512 (2004).
Koumenis, C. & Giaccia, A. Transformed cells require continuous activity of RNA polymerase II to resist oncogene-induced apoptosis. Mol. Cell. Biol. 17, 7306–7316 (1997).
Poele, R. H. T., Okorokov, A. L. & Joel, S. P. RNA synthesis block by 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) triggers p53-dependent apoptosis in human colon carcinoma cells. Oncogene 18, 5765–5772 (1999).
Rubbi, C. P. & Milner, J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J. 22, 6068–6077 (2003).
Sherr, C. J. & Weber, J. D. The ARF/p53 pathway. Curr. Opin. Genet. Devel. 10, 94–99 (2000).
Zhang, Y. & Xiong, Y. Control of p53 Ubiquitination and nuclear export by MDM2 and ARF. Cell Growth Diff. 12, 175–186 (2001).
Benavente, R., Reimer, G., Rose, K. M., Hugle-Dorr, B. & Scheer, U. Nucleolar changes after microinjection of antibodies to RNA polymerase I into the nucleus of mammalian cells. Chromosoma 97, 115–123 (1988).
Haaf, T. & Ward, D. C. Inhibition of RNA polymerase II transcription causes chromatin decondensation, loss of nucleolar structure, and dispersion of chromosomal domains. Exp. Cell Res. 224, 163–173 (1996).
O'Hagan, H. M. & Ljungman, M. Efficient NES-dependent protein nuclear export requires ongoing synthesis and export of mRNAs. Exp. Cell Res. 297, 548–559 (2004).
Stommel, J. M. et al. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J. 18, 1660–1672 (1999).
Zhang, Y. P. & Xiong, Y. A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation. Science 292, 1910–1915 (2001).
Yoshida, Y. et al. Binding of RNA to p53 regulates its oligomerization and DNA–binding activity. Oncogene 23, 4371–4379 (2004).
McKay, B. C. et al. Regulation of ultraviolet light-induced gene expression by gene size. Proc. Natl Acad. Sci. USA 101, 6582–6586 (2004).
Billecke, C. A. et al. Lack of functional pRb results in attenuated recovery of mRNA synthesis and increased apoptosis following UV radiation in human breast cancer cells. Oncogene 21, 4481–4489 (2002).
McKay, B. C., Chen, F., Perumalswami, C. R., Zhang, F. F. & Ljungman, M. The tumor suppressor p53 can both stimulate and inhibit ultraviolet light-induced apoptosis. Mol. Biol. Cell 11, 2543–2551 (2000).
McKay, B. & Ljungman, M. Role for p53 in the recovery of transcription and protection against apoptosis induced by ultraviolet light. Neoplasia 1, 276–284 (1999).
Proietti De Santis, L. et al. Inhibition of p53, p21 and Bax by pifithrin-α does not affect UV induced apoptotic response in CS-B cells. DNA Repair 2, 891–900 (2003).
Chouinard, N., Valerie, K., Rouabhia, M. & Huot, J. UVB-mediated activation of p38 mitogen-activated protein kinase enhances resistance of normal human keratinocytes to apoptosis by stabilizing cytoplasmic p53. Biochem. J. 365, 133–145 (2002).
McKay, B., Becerril, C., Spronck, J. & Ljungman, M. Ultraviolet light-induced apoptosis is associated with S-phase in primary human fibroblasts. DNA Repair 1, 811–820 (2002).
McGlynn, P. & Lloyd, R. G. Recombinational repair and restart of damaged replication forks. Nature Rev. Mol. Cell Biol. 3, 859–870 (2002).
Bissonnette, N. & Hunting, D. J. p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage. Oncogene 16, 3461–3469 (1998).
Porter, L. A., Cukier, I. H. & Lee, J. M. Nuclear localization of cyclin B1 regulates DNA damage-induced apoptosis. Blood 101, 1928–1933 (2003).
Viswanathan, A. & Doetsch, P. W. Effects of nonbulky DNA base damages on Escherichia coli RNA polymerase-mediated elongation and promoter clearance. J. Biol. Chem. 273, 21276–21281 (1998).
Tornaletti, S., Maeda, L. S., Lloyd, D. R., Reines, D. & Hanawalt, P. C. Effect of thymine glycol on transcription elongation by T7 RNA polymerase and mammalian RNA polymerase II. J. Biol. Chem. 276, 45367–45371 (2001).
Tornaletti, S., Maeda, L. S., Kolodner, R. D. & Hanawalt, P. C. Effect of 8-oxoguanine on transcription elongation by T7 RNA polymerase and mammalian RNA polymerase II. DNA Repair (Amst) 3, 483–494 (2004).
Le Page, F. et al. Transcription-coupled repair of 8-oxoGuanine: Requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome. Cell 101, 159–171 (2000).
Yanamadala, S. & Ljungman, M. Potential role of MLH1 in the induction of p53 and apoptosis by blocking transcription on damaged DNA templates. Mol. Cancer Res. 1, 747–754 (2003).
Duckett, D. R. et al. Human MutSα recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct. Proc. Natl Acad. Sci. USA 93, 6443–6447 (1996).
Bellacosa, A. Functional interactions and signaling properties of mammalian DNA mismatch repair proteins. Cell Death Differ. 8, 1076–1092 (2001).
Duckett, D. R., Bronstein, S. M., Taya, Y. & Modrich, P. hMutSα- and hMutLα-dependent phosphorylation of p53 in response to DNA methylator damage. Proc. Natl Acad. Sci. USA 96, 12384–12388 (1999).
Hickman, M. J. & Samson, L. D. Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents. Proc. Natl Acad. Sci. USA 96, 10764–10769 (1999).
Donahue, B. A., Yin, S., Taylor, J. S., Reines, D. & Hanawalt, P. C. Transcript cleavage by RNA polymerase II arrested by a cyclobutane pyrimidine dimer in the DNA template. Proc. Natl Acad. Sci. USA 91, 8502–8506 (1994).
Tornaletti, S., Reines, D. & Hanawalt, P. C. Structural characterization of RNA polymerase II complexes arrested by a cyclobutane pyrimidine dimer in the transcribed strand of template DNA. J. Biol. Chem. 274, 24124–24130 (1999).
Sauerbier, W. & Hercules, K. Gene and transcription mapping by radiation effects. Annu. Rev. Genet. 12, 329–363 (1978).
Ljungman, M. Recovery of RNA synthesis from the DHFR gene following UV-irradiation precedes the removal of photolesions from the transcribed strand. Carcinogenesis 20, 395–399 (1999).
Leadon, S. & Snowden, M. Differential repair of DNA damage in the human metallothionein gene family. Mol. Cell. Biol. 8, 5331–5338 (1988).
Doetsch, P. W. Translesion synthesis by RNA polymerases: occurrence and biological implications for transcriptional mutagenesis. Mutat. Res. 510, 131–140 (2002).
van Hoffen, A. et al. Deficient repair of the transcribed strand of active genes in Cockayne's syndrome cells. Nucleic Acids Res. 21, 5890–5895 (1993).
Leadon, S. A. & Cooper, P. K. Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome. Proc. Natl Acad. Sci. USA 90, 10499–10503 (1993).
Mellon, I., Rajpal, D. K., Koi, M., Boland, C. R. & Champe, G. N. Transcription-coupled repair deficiency and mutations in human mismatch repair genes. Science 272, 557–560 (1996).
Nakatsu, Y. et al. XAB2, a novel tetratricopeptide repeat protein involved in transcription-coupled DNA repair and transcription. J. Biol. Chem. 275, 34931–34937 (2000).
Abbott, D. W. et al. BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J. Biol. Chem. 274, 18808–18812 (1999).
Le Page, F. et al. BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res. 60, 5548–5552 (2000).
Furuta, T. et al. Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. Cancer Res. 62, 4899–4902 (2002).
de Boer, J. & Hoeijmakers, J. H. J. Nucleotide excision repair and human syndromes. Carcinogenesis 21, 453–460 (2000).
Lu, Y. et al. Disruption of the Cockayne syndrome B gene impairs spontaneous tumorigenesis in cancer-predisposed Ink4a/ARF knockout mice. Mol. Cell. Biol. 21, 1810–1818 (2001).
Takebayashi, Y. et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nature Med. 7, 961–966 (2001).
Jaspers, N. G. J. et al. Anti-tumour compounds illudin S and Irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription- and replication-coupled repair pathways. DNA Repair 1, 1027–1038 (2002).
Ljungman, M. & Hanawalt, P. C. The anti-cancer drug camptothecin inhibits elongation but stimulates initiation of RNA polymerase II transcription. Carcinogenesis 17, 31–35 (1996).
Ratner, J. N., Balasubramanian, B., Corden, J., Warren, S. L. & Bregman, D. B. Ultraviolet radiation-induced ubiquitination and proteasomal degradation of the large subunit of RNA polymerase II — implications for transcription-coupled DNA repair. J. Biol. Chem. 273, 5184–5189 (1998).
Bregman, D. B. et al. UV-induced ubiquitination of RNA polymerase II: A novel modification deficient in cockayne syndrome cells. Proc. Natl Acad. Sci. USA 93, 11586–11590 (1996).
McKay, B. C. et al. UV light-induced degradation of RNA polymerase II is dependent on the Cockayne's syndrome A and B proteins but not p53 or MLH1. Mutat. Res. 485, 93–105 (2001).
Lee, K. B., Wang, D., Lippard, S. J. & Sharp, P. A. Transcription-coupled and DNA damage dependent ubiquitination of RNA polymerase II in vitro. Proc. Natl Acad. Sci. USA 99, 4239–4244 (2002).
Yang, L. Y., Jiang, H. & Rangel, K. M. RNA polymerase II stalled on a DNA template during transcription elongation is ubiquitinated and the ubiquitination facilitates displacement of the elongation complex. Int. J. Oncol. 22, 683–689 (2003).
Gillette, T. G., Gonzalez, F., Delahodde, A., Johnston, S. A. & Kodadek, T. Physical and functional association of RNA polymerase II and the proteasome. Proc. Natl Acad. Sci. USA 101, 5904–5909 (2004).
Iwai, K. et al. Identification of the von Hippel–Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc. Natl Acad. Sci. USA 96, 12436–12441 (1999).
Kuznetsova, A. V. et al. von Hippel–Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination. Proc. Natl Acad. Sci. USA 100, 2706–2711 (2003).
Schoenfeld, A. R. et al. The von Hippel–Lindau tumor suppressor gene protects cells from UV-mediated apoptosis. Oncogene 19, 5851–5857 (2000).
Luo, Z. H., Zheng, J. H., Lu, Y. & Bregman, D. B. Ultraviolet radiation alters the phosphorylation of RNA polymerase II large subunit and accelerates its proteasome-dependent degradation. Mutat. Res. 486, 259–274 (2001).
Groisman, R. et al. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113, 357–367 (2003).
Scully, R. et al. BRCA1 is a component of the RNA polymerase II holoenzyme. Proc. Natl Acad. Sci. USA 94, 5605–5610 (1997).
Chiba, N. & Parvin, J. D. The BRCA1 and BARD1 association with the RNA polymerase II holoenzyme. Cancer Res. 62, 4222–4228 (2002).
Krum, S. A., Miranda, G. A., Lin, C. & Lane, T. F. BRCA1 associates with processive RNA polymerase II. J. Biol. Chem. 278, 52012–52020 (2003).
Rolig, R. L. & McKinnon, P. J. Linking DNA damage and neurodegeneration. Trends Neurosci. 23, 417–424 (2000).
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003).
Balajee, A. S. et al. The Werner syndrome protein is involved in RNA polymerase II transcription. Mol. Biol. Cell 10, 2655–2668 (1999).
Lee, S. K., Johnson, R. E., Yu, S. L., Prakash, L. & Prakash, S. Requirement of yeast SGS1 and SRS2 genes for replication and transcription. Science 286, 2339–2342 (1999).
Furuichi, Y. Premature aging and predisposition to cancers caused by mutations in RecQ family helicases. Ann. NY Acad. Sci. 928, 121–131 (2001).
Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423, 293–298 (2003).
Mounkes, L. C., Kozlov, S., Hernandez, L., Sullivan, T. & Stewart, C. L. A progeroid syndrome in mice is caused by defects in A-type lamins. Nature 423, 298–301 (2003).
Spann, T. P., Goldman, A. E., Wang, C., Huang, S. & Goldman, R. D. Alteration of nuclear lamin organization inhibits RNA polymerase II-dependent transcription. J. Cell Biol. 156, 603–608 (2002).
Kumaran, R. I., Muralikrishna, B. & Parnaik, V. K. Lamin A/C speckles mediate spatial organization of splicing factor compartments and RNA polymerase II transcription. J. Cell Biol. 159, 783–793 (2002).
Vogel, H., Lim, D. S., Karsenty, G., Finegold, M. & Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl Acad. Sci. USA 96, 10770–10775 (1999).
Woodard, R. L., Lee, K. J., Huang, J. & Dynan, W. S. Distinct roles for Ku protein in transcriptional reinitiation and DNA repair. J. Biol. Chem. 276, 15423–15433 (2001).
Mo, X. M. & Dynan, W. S. Subnuclear localization of Ku protein: Functional association with RNA polymerase II elongation sites. Mol. Cell. Biol. 22, 8088–8099 (2002).
Bertinato, J., Tomlinson, J. J., Schild-Poulter, C. & Hache, R. J. G. Evidence implicating Ku antigen as a structural factor in RNA polymerase II-mediated transcription. Gene 302, 53–64 (2003).
Chang, T. C. et al. Effects of transcription and translation inhibitors on a human gastric carcinoma cell line- Potential role of Bcl-X-s in apoptosis triggered by these inhibitors. Biochem. Pharmacol. 53, 969–977 (1997).
Chang, D., Chen, F., Zhang, F. F., McKay, B. C. & Ljungman, M. Dose-dependent effects of DNA-damaging agents on p53-mediated cell cycle arrest. Cell Growth Differ. 10, 155–162 (1999).
Collins, I., Weber, A. & Levens, D. Transcriptional consequences of topoisomerase inhibition. Mol. Cell. Biol. 21, 8437–8451 (2001).
Squires, S., Ryan, A. J., Strutt, H. L. & Johnson, R. T. Hypersensitivity of Cockayne's syndrome cells to camptothecin is associated with the generation of abnormally high levels of double strand breaks in nascent DNA. Cancer Res. 53, 2012–2019 (1993).
Geoffroy, F. J., Allegra, C. J., Sinha, B. & Grem, J. L. Enhanced cytotoxicity with interleukin-1 alpha and 5-fluorouracil in HCT116 colon cancer cells. Oncol. Res. 6, 581–591 (1994).
Pritchard, D. M., Watson, A. J. M., Potten, C. S., Jackman, A. L. & Hickman, J. A. Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation. Proc. Natl Acad. Sci. USA 94, 1795–1799 (1997).
Huang, P., Sandoval, A., Van Den Neste, E., Keating, M. J. & Plunkett, W. Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine. Leukemia 14, 1405–1413 (2000).
McClue, S. J. et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int. J. Cancer 102, 463–468 (2002).
Senderowicz, A. M. Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. Cancer Chemother. Pharmacol. 52, 61–73 (2003).
Ljungman, M. & Paulsen, M. T. The cyclin-dependent kinase inhibitor roscovitine inhibits RNA synthesis and triggers nuclear accumulation of p53 that is unmodified at Ser15 and Lys382. Mol. Pharm. 60, 785–789 (2001).
Lam, L. T. et al. Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol. 2, 1–11 (2001).
Gojo, I., Zhang, B. & Fenton, R. G. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1. Clin. Cancer Res. 8, 3527–3538 (2002).
Hietanen, S., Lain, S., Krausz, E., Blattner, C. & Lane, D. P. Activation of p53 in cervical carcinoma cells by small molecules. Proc. Natl Acad. Sci. USA 97, 8501–8506 (2000).
Blaydes, J. P. et al. Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways. Oncogene 19, 3829–3839 (2000).
Maggiorella, L. et al. Enhancement of radiation response by roscovitine in human breast carcinoma in vitro and in vivo. Cancer Res. 63, 2513–2517 (2003).
Lain, S. & Lane, D. Improving cancer therapy by non-genotoxic activation of p53. Eur. J. Cancer 39, 1053–1060 (2003).
Woods, Y. L. & Lane, D. P. Exploiting the p53 pathway for cancer diagnosis and therapy. Hematol. J. 4, 233–247 (2003).
Laín, S., Xirodimas, D. & Lane, D. P. Accumulating active p53 in the nucleus by inhibition of nuclear export: A novel strategy to promote the p53 tumor suppressor function. Exp. Cell Res. 253, 315–324 (1999).
Lane, D. P. Exploiting the p53 pathway for cancer diagnosis and therapy. Br. J. Cancer 80, 1–5 (1999).
Lane, D. P. & Lain, S. Therapeutic exploitation of the p53 pathway. Trends Mol. Med. 8, S38–S42 (2002).
Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).
Abraham, R. T. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15, 2177–2196 (2001).
Brumbaugh, K. M. et al. The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells. Mol. Cell 14, 585–598 (2004).
Venkitaraman, A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108, 171–182 (2002).
Xu, B., Kim, S. T. & Kastan, M. B. Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol. Cell. Biol. 21, 3445–3450 (2001).
Tibbetts, R. S. et al. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev. 14, 2989–3002 (2000).
Gatei, M. et al. Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies. J. Biol. Chem. 276, 17276–17280 (2001).
Deng, C. X. & Brodie, S. G. Roles of BRCA1 and its interacting proteins. Bioessays 22, 728–737 2000).
Scully, R. & Livingston, D. M. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 408, 429–432 (2000).
Acknowledgements
We would like to thank The National Institute of Health, The Swedish Cancer Foundation, Cancer Research UK and the American Institute for Cancer Research for financial support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Ljungman, M., Lane, D. Transcription — guarding the genome by sensing DNA damage. Nat Rev Cancer 4, 727–737 (2004). https://doi.org/10.1038/nrc1435
Issue Date:
DOI: https://doi.org/10.1038/nrc1435
This article is cited by
-
Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress
Nature Communications (2023)
-
Interface of DNA Repair and Metabolism
Current Tissue Microenvironment Reports (2020)
-
Topological DNA damage, telomere attrition and T cell senescence during chronic viral infections
Immunity & Ageing (2019)
-
Gene ontology analysis of expanded porcine blastocysts from gilts fed organic or inorganic selenium combined with pyridoxine
BMC Genomics (2018)
-
DNA damage and the balance between survival and death in cancer biology
Nature Reviews Cancer (2016)