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Nucleic Acids Research 2006 34(1):140-151; doi:10.1093/nar/gkj430
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Published online 10 January 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Linking uracil base excision repair and 5-fluorouracil toxicity in yeast

Lauren Seiple, Pawel Jaruga1,2, Miral Dizdaroglu2 and James T. Stivers*

Department of Pharmacology and Molecular Sciences Johns Hopkins University School of Medicine 725 North Wolfe Street Baltimore, MD 21205, USA 1Department of Chemical and Biochemical Engineering, University of Maryland Baltimore County Baltimore, MD 21225, USA 2Chemical Science and Technology Laboratory, National Institute of Standards and Technology Gaithersburg MD 20899, USA

*To whom correspondence should be addressed. Tel: +1 410 502 2758; Fax: +1 410 955 3023; Email: jstivers{at}jhmi.edu

Received September 20, 2005. Revised December 2, 2005. Accepted December 16, 2005.

5-fluorouracil (5-FU) is a widely used anticancer drug that disrupts pyrimidine nucleotide pool balances and leads to uracil incorporation in DNA, which is then recognized and removed by the uracil base excision repair (BER) pathway. Using complementary biochemical and genetic approaches we have examined the role of uracil BER in the cell killing mechanism of 5-FU. A yeast strain lacking the enzyme uracil DNA glycosylase (Ung1), which excises uracil from the DNA backbone leaving an abasic site, showed significant protection against the toxic effects of 5-FU, a G1/S cell cycle arrest phenotype, and accumulated massive amounts of U/A base pairs in its genome (~4% of T/A pairs were now U/A). A strain lacking the major abasic site endonuclease of Saccharomyces cerevisiae (Apn1) showed significantly increased sensitivity to 5-FU with G2/M arrest. Thus, efficient processing of abasic sites by this enzyme is protective against the toxic effects of 5-FU. However, contrary to expectations, the Apn1 deficient strain did not accumulate intact abasic sites, indicating that another repair pathway attempts to process these sites in the absence Apn1, but that this process has catastrophic effects on genome integrity. These findings suggest that new strategies for chemical intervention targeting BER could enhance the effectiveness of this widely used anticancer drug.


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