A compromised yeast RNA Polymerase II enhances UV sensitivity in the absence of global genome nucleotide excision repair
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O R I GI N A L P A P E R
J. M. S. Wong á C. J. Ingles
A compromised yeast RNA Polymerase II enhances UV sensitivity in the absence of global genome nucleotide excision repair
Received: 9 June 2000 / Accepted: 9 July 2000 / Published online: 10 November 2000 Ó Springer-Verlag 2000
Abstract Nucleotide excision repair is the major pathway responsible for removing UV-induced DNA damage, and is therefore essential for cell survival following exposure to UV radiation. In this report, we have assessed the contributions of some components of the RNA polymerase II (Pol II) transcription machinery to UV resistance in Saccharomyces cerevisiae. Deletion of the gene encoding the Pol II elongation factor TFIIS (SII) resulted in enhanced UV sensitivity, but only in the absence of global genome repair dependent on the RAD7 and RAD16 genes, a result seen previously with deletions of RAD26 and RAD28, yeast homologs of the human Cockayne syndrome genes CSB and CSA, respectively. A RAD7/16-dependent reduction in survival after UV irradiation was also seen in the presence of mutations in RNA Pol II that confer a defect in its response to SII, as well as with other mutations which reside in regions of the largest subunit of Pol II not involved in SII interactions. Indeed, an increase in UV sensitivity was achieved by simply decreasing the steadystate level of RNA Pol II. Truncation of the C-terminal domain and other RNA Pol II mutations conferred sensitivity to the ribonucleotide reductase inhibitor hydroxyurea and induction of RNR1 and RNR2 mRNAs after UV irradiation was attenuated in these mutant cells. That UV sensitivity can be a consequence of mutations in the RNA Pol II machinery in yeast cells suggests that alterations in transcriptional programs could
Communicated by D. Y. Thomas J. M. S. Wong á C. J. Ingles (&) Banting and Best Department of Medical Research, University of Toronto, 112 College Street, Toronto, Ontario, Canada M5G 1L6 E-mail: [email protected] Tel.: +1-416-978-7400 Fax: +1-416-978-8528 J. M. S. Wong á C. J. Ingles Department of Molecular and Medical Genetics, University of Toronto, Ontario, Canada M5G 1L6
underlie some of the pathophysiological defects seen in the human disease Cockayne syndrome. Key words Nucleotide excision repair á RNA polymerase II á Transcription elongation factor SII (TFIIS)
Introduction Multiple DNA repair pathways have evolved to repair dierent types of DNA lesions. Nucleotide excision repair (NER), one of the most versatile of these pathways, is capable of removing a variety of helix-distorting lesions, including cyclobutane pyrimidine dimers and 6-4 photoproducts induced by UV radiation, as well as bulky chemical adducts (Friedberg 1996; Sancar 1996; Wood 1996, 1997). One distinctive feature of NER is its variability in the rate of repair across the genome. Damage in transcriptionally silent genes and in the nontranscribed strands of actively transcribed genes is processed by the NER subpathway for global genomic repair, which in Saccharomyces cerevisiae is dependent on both
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