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J. Biol. Chem., Vol. 278, Issue 37, 35791-35797, September 12, 2003

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Behavior of T7 RNA Polymerase and Mammalian RNA Polymerase II at Site-specific Cisplatin Adducts in the Template DNA^*

Silvia Tornaletti , Steve M. Patrick , John J. Turchi  and Philip C. Hanawalt  ¶

From the Department of Biological Sciences, Stanford University, Stanford, California 94305-5020 and the Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, Ohio 45435

Transcription-coupled DNA repair is dedicated to the removal of DNA lesions from transcribed strands of expressed genes. RNA polymerase arrest at a lesion has been proposed as a sensitive signal for recruitment of repair enzymes to the lesion site. To understand how initiation of transcription-coupled repair may occur, we have characterized the properties of the transcription complex when it encounters a lesion in its path. Here we have compared the effect of cisplatin-induced intrastrand cross-links on transcription elongation by T7 RNA polymerase and mammalian RNA polymerase II. We found that a single cisplatin 1,2-d(GG) intrastrand cross-link or a single cisplatin 1,3-d(GTG) intrastrand cross-link is a strong block to both polymerases. Furthermore, the efficiency of the block at a cisplatin 1,2-d(GG) intrastrand cross-link was similar in several different nucleotide sequence contexts. Interestingly, some blockage was also observed when the single cisplatin 1,3-d(GTG) intrastrand cross-link was located in the non-transcribed strand. Transcription complexes arrested at the cisplatin adducts were substrates for the transcript cleavage reaction mediated by the elongation factor TFIIS, indicating that the RNA polymerase II complexes arrested at these lesions are not released from template DNA. Addition of TFIIS yielded a population of transcripts up to 30 nucleotides shorter than those arrested at the lesion. In the presence of nucleoside triphosphates, these shortened transcripts could be re-elongated up to the site of the lesion, indicating that the arrested complexes are stable and competent to resume elongation. These results show that cisplatin-induced lesions in the transcribed DNA strand constitute a strong physical barrier to RNA polymerase progression, and they support current models of transcription arrest and initiation of transcription-coupled repair.

Received for publication, May 22, 2003 , and in revised form, June 19, 2003.

^* This work was supported by Grant CA-77712 from the National Cancer Institute, U.S. Department of Health and Human Services (to P. C. H.), and by Grant CA82741 from the National Institutes of Health (to J. J. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 650-723-2424; Fax: 650-725-1848; E-mail: hanawalt{at}stanford.edu.

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