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Nucleic Acids Research 2006 34(7):2056-2066; doi:10.1093/nar/gkl139
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Published online 14 April 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@oxfordjournals.org

Article

dUTPase activity is critical to maintain genetic stability in Saccharomyces cerevisiae

Marie Guillet*, Patricia Auffret Van Der Kemp and Serge Boiteux

CEA, DSV Département de Radiobiologie et Radiopathologie, UMR 217 CNRS ‘Radiobiologie Moléculaire et Cellulaire’ BP 6, 92265 Fontenay aux Roses, France

*To whom correspondence should be addressed. Tel: +1 617 632 4343; Fax: +1 617 632 6845; Email: marie_guillet{at}dfci.harvard.edu

Received February 1, 2006. Revised February 28, 2006. Accepted March 15, 2006.

We identified a viable allele (dut1-1) of the DUT1 gene that encodes the dUTPase activity in Saccharomyces cerevisiae. The Dut1-1 protein possesses a single amino acid substitution (Gly82Ser) in a conserved motif nearby the active site and exhibits a greatly reduced dUTPase activity. The dut1-1 single mutant exhibits growth delay and cell cycle abnormalities and shows a strong spontaneous mutator phenotype. All phenotypes of the dut1-1 mutant are suppressed by the simultaneous inactivation of the uracil DNA N-glycosylase, Ung1. However, the ung1 dut1-1 double mutant accumulates uracil in its genomic DNA. The viability of the dut1-1 mutant is greatly impaired by the simultaneous inactivation of AP endonucleases. These data strongly suggest that the phenotypes of the dut1-1 mutant result from the incorporation of dUMPs into DNA subsequently converted into AP sites. The analysis of the dut1-1 strain mutation spectrum showed that cytosines are preferentially incorporated in front of AP sites in a Rev3-dependent manner during translesion synthesis. These results point to a critical role of the Dut1 protein in the maintenance of the genetic stability. Therefore, the normal cellular metabolism, and not only its byproducts, is an important source of endogenous DNA damage and genetic instability in eukaryotic cells.

Present address: M. Guillet, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA

Correspondence may also be addressed to Serge Boiteux. Tel: +33 1 46 54 88 58; Fax: +33 1 46 54 88 59; Email: serge.boiteux{at}cea.fr


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