Abstract
Cis -diammininedichloroplatinum(II) (cisplatin or cis -DDP) is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin crosslinks DNA and the resulting adducts interact with proteins that contain high-mobility-group (HMG) domains, such as UBF(upstream binding factor). UBF is a transcription factor that binds to the promoter of ribosomal RNA (rRNA) genes thereby supporting initiation of transcription by RNA polymerase I. Here we report that cisplatin causes a redistribution of UBF in the nucleolus of human cells, similar to that observed after inhibition of rRNA synthesis. A similar redistribution was observed for the major components of the rRNA transcription machinery, namely TBP, TAFIs and RNA polymerase I. Furthermore, we provide for the first time direct in vivo evidence that cisplatin blocks synthesis of rRNA, while activity of RNA polymerase II continues to be detected throughout the nucleus. The clinically ineffective trans isomer (trans -DDP) does not alter the localization of either UBF or other components of the RNA polymerase I transcription machinery. These results suggest that disruption of rRNA synthesis, which is stimulated in proliferating cells, plays an important role in the clinical success of cisplatin.
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- Bazett-Jones D. P., Leblanc B., Herfort M., Moss T. Short-range DNA looping by the Xenopus HMG-box transcription factor, xUBF. Science. 1994 May 20;264(5162):1134–1137. doi: 10.1126/science.8178172. [DOI] [PubMed] [Google Scholar]
- Bell S. P., Learned R. M., Jantzen H. M., Tjian R. Functional cooperativity between transcription factors UBF1 and SL1 mediates human ribosomal RNA synthesis. Science. 1988 Sep 2;241(4870):1192–1197. doi: 10.1126/science.3413483. [DOI] [PubMed] [Google Scholar]
- Brown S. J., Kellett P. J., Lippard S. J. Ixr1, a yeast protein that binds to platinated DNA and confers sensitivity to cisplatin. Science. 1993 Jul 30;261(5121):603–605. doi: 10.1126/science.8342024. [DOI] [PubMed] [Google Scholar]
- Carmo-Fonseca M., Cunha C., Custódio N., Carvalho C., Jordan P., Ferreira J., Parreira L. The topography of chromosomes and genes in the nucleus. Exp Cell Res. 1996 Dec 15;229(2):247–252. doi: 10.1006/excr.1996.0367. [DOI] [PubMed] [Google Scholar]
- Chao J. C., Wan X. S., Engelsberg B. N., Rothblum L. I., Billings P. C. Intracellular distribution of HMG1, HMG2 and UBF change following treatment with cisplatin. Biochim Biophys Acta. 1996 Jun 7;1307(2):213–219. doi: 10.1016/0167-4781(96)00052-8. [DOI] [PubMed] [Google Scholar]
- Chow C. S., Whitehead J. P., Lippard S. J. HMG domain proteins induce sharp bends in cisplatin-modified DNA. Biochemistry. 1994 Dec 20;33(50):15124–15130. doi: 10.1021/bi00254a023. [DOI] [PubMed] [Google Scholar]
- Codony-Servat J., Gimeno R., Gelpi C., Rodriguez-Sanchez J. L., Juarez C. The two isoforms of the 90-kDalton nucleolus organizer region autoantigen (upstream binding factor) bind with different avidity to DNA modified by the antitumor drug cisplatin. Biochem Pharmacol. 1996 May 3;51(9):1131–1136. doi: 10.1016/0006-2952(95)02441-7. [DOI] [PubMed] [Google Scholar]
- Comai L., Zomerdijk J. C., Beckmann H., Zhou S., Admon A., Tjian R. Reconstitution of transcription factor SL1: exclusive binding of TBP by SL1 or TFIID subunits. Science. 1994 Dec 23;266(5193):1966–1972. doi: 10.1126/science.7801123. [DOI] [PubMed] [Google Scholar]
- Corda Y., Anin M. F., Leng M., Job D. RNA polymerases react differently at d(ApG) and d(GpG) adducts in DNA modified by cis-diamminedichloroplatinum(II). Biochemistry. 1992 Feb 25;31(7):1904–1908. doi: 10.1021/bi00122a002. [DOI] [PubMed] [Google Scholar]
- Corda Y., Job C., Anin M. F., Leng M., Job D. Transcription by eucaryotic and procaryotic RNA polymerases of DNA modified at a d(GG) or a d(AG) site by the antitumor drug cis-diamminedichloroplatinum(II). Biochemistry. 1991 Jan 8;30(1):222–230. doi: 10.1021/bi00215a032. [DOI] [PubMed] [Google Scholar]
- Fey E. G., Krochmalnic G., Penman S. The nonchromatin substructures of the nucleus: the ribonucleoprotein (RNP)-containing and RNP-depleted matrices analyzed by sequential fractionation and resinless section electron microscopy. J Cell Biol. 1986 May;102(5):1654–1665. doi: 10.1083/jcb.102.5.1654. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grosschedl R., Giese K., Pagel J. HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet. 1994 Mar;10(3):94–100. doi: 10.1016/0168-9525(94)90232-1. [DOI] [PubMed] [Google Scholar]
- Hisatake K., Nishimura T., Maeda Y., Hanada K., Song C. Z., Muramatsu M. Cloning and structural analysis of cDNA and the gene for mouse transcription factor UBF. Nucleic Acids Res. 1991 Sep 11;19(17):4631–4637. doi: 10.1093/nar/19.17.4631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jackson D. A., Hassan A. B., Errington R. J., Cook P. R. Visualization of focal sites of transcription within human nuclei. EMBO J. 1993 Mar;12(3):1059–1065. doi: 10.1002/j.1460-2075.1993.tb05747.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jantzen H. M., Admon A., Bell S. P., Tjian R. Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins. Nature. 1990 Apr 26;344(6269):830–836. doi: 10.1038/344830a0. [DOI] [PubMed] [Google Scholar]
- Jordan P., Mannervik M., Tora L., Carmo-Fonseca M. In vivo evidence that TATA-binding protein/SL1 colocalizes with UBF and RNA polymerase I when rRNA synthesis is either active or inactive. J Cell Biol. 1996 Apr;133(2):225–234. doi: 10.1083/jcb.133.2.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Loehrer P. J., Einhorn L. H. Drugs five years later. Cisplatin. Ann Intern Med. 1984 May;100(5):704–713. doi: 10.7326/0003-4819-100-5-704. [DOI] [PubMed] [Google Scholar]
- Mello J. A., Lippard S. J., Essigmann J. M. DNA adducts of cis-diamminedichloroplatinum(II) and its trans isomer inhibit RNA polymerase II differentially in vivo. Biochemistry. 1995 Nov 14;34(45):14783–14791. doi: 10.1021/bi00045a020. [DOI] [PubMed] [Google Scholar]
- Metz R., Kouzarides T., Bravo R. A C-terminal domain in FosB, absent in FosB/SF and Fra-1, which is able to interact with the TATA binding protein, is required for altered cell growth. EMBO J. 1994 Aug 15;13(16):3832–3842. doi: 10.1002/j.1460-2075.1994.tb06694.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moss T., Stefanovsky V. Y. Promotion and regulation of ribosomal transcription in eukaryotes by RNA polymerase I. Prog Nucleic Acid Res Mol Biol. 1995;50:25–66. doi: 10.1016/s0079-6603(08)60810-7. [DOI] [PubMed] [Google Scholar]
- Mymryk J. S., Zaniewski E., Archer T. K. Cisplatin inhibits chromatin remodeling, transcription factor binding, and transcription from the mouse mammary tumor virus promoter in vivo. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2076–2080. doi: 10.1073/pnas.92.6.2076. [DOI] [PMC free article] [PubMed] [Google Scholar]
- O'Mahony D. J., Rothblum L. I. Identification of two forms of the RNA polymerase I transcription factor UBF. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3180–3184. doi: 10.1073/pnas.88.8.3180. [DOI] [PMC free article] [PubMed] [Google Scholar]
- O'Mahony D. J., Xie W. Q., Smith S. D., Singer H. A., Rothblum L. I. Differential phosphorylation and localization of the transcription factor UBF in vivo in response to serum deprivation. In vitro dephosphorylation of UBF reduces its transactivation properties. J Biol Chem. 1992 Jan 5;267(1):35–38. [PubMed] [Google Scholar]
- Pombo A., Ferreira J., Bridge E., Carmo-Fonseca M. Adenovirus replication and transcription sites are spatially separated in the nucleus of infected cells. EMBO J. 1994 Nov 1;13(21):5075–5085. doi: 10.1002/j.1460-2075.1994.tb06837.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- ROSENBERG B., VANCAMP L., KRIGAS T. INHIBITION OF CELL DIVISION IN ESCHERICHIA COLI BY ELECTROLYSIS PRODUCTS FROM A PLATINUM ELECTRODE. Nature. 1965 Feb 13;205:698–699. doi: 10.1038/205698a0. [DOI] [PubMed] [Google Scholar]
- Rothblum L. I., Parker D. L., Cassidy B. Isolation and characterization of rat ribosomal DNA clones. Gene. 1982 Jan;17(1):75–77. doi: 10.1016/0378-1119(82)90102-0. [DOI] [PubMed] [Google Scholar]
- Roussel P., André C., Comai L., Hernandez-Verdun D. The rDNA transcription machinery is assembled during mitosis in active NORs and absent in inactive NORs. J Cell Biol. 1996 Apr;133(2):235–246. doi: 10.1083/jcb.133.2.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schnapp A., Grummt I. Transcription complex formation at the mouse rDNA promoter involves the stepwise association of four transcription factors and RNA polymerase I. J Biol Chem. 1991 Dec 25;266(36):24588–24595. [PubMed] [Google Scholar]
- Treiber D. K., Zhai X., Jantzen H. M., Essigmann J. M. Cisplatin-DNA adducts are molecular decoys for the ribosomal RNA transcription factor hUBF (human upstream binding factor). Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5672–5676. doi: 10.1073/pnas.91.12.5672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vichi P., Coin F., Renaud J. P., Vermeulen W., Hoeijmakers J. H., Moras D., Egly J. M. Cisplatin- and UV-damaged DNA lure the basal transcription factor TFIID/TBP. EMBO J. 1997 Dec 15;16(24):7444–7456. doi: 10.1093/emboj/16.24.7444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wansink D. G., Schul W., van der Kraan I., van Steensel B., van Driel R., de Jong L. Fluorescent labeling of nascent RNA reveals transcription by RNA polymerase II in domains scattered throughout the nucleus. J Cell Biol. 1993 Jul;122(2):283–293. doi: 10.1083/jcb.122.2.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zamble D. B., Lippard S. J. Cisplatin and DNA repair in cancer chemotherapy. Trends Biochem Sci. 1995 Oct;20(10):435–439. doi: 10.1016/s0968-0004(00)89095-7. [DOI] [PubMed] [Google Scholar]
- Zatsepina O. V., Voit R., Grummt I., Spring H., Semenov M. V., Trendelenburg M. F. The RNA polymerase I-specific transcription initiation factor UBF is associated with transcriptionally active and inactive ribosomal genes. Chromosoma. 1993 Nov;102(9):599–611. doi: 10.1007/BF00352307. [DOI] [PubMed] [Google Scholar]
- Zeng C., Kim E., Warren S. L., Berget S. M. Dynamic relocation of transcription and splicing factors dependent upon transcriptional activity. EMBO J. 1997 Mar 17;16(6):1401–1412. doi: 10.1093/emboj/16.6.1401. [DOI] [PMC free article] [PubMed] [Google Scholar]