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Nucleic Acids Research Advance Access originally published online on September 4, 2008
Nucleic Acids Research 2008 36(17):5660-5667; doi:10.1093/nar/gkn555
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Nucleic Acids Research, 2008, Vol. 36, No. 17 5660-5667
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome integrity, repair and replication

Evidence for lesion bypass by yeast replicative DNA polymerases during DNA damage

Nasim Sabouri, Jörgen Viberg, Dinesh Kumar Goyal, Erik Johansson and Andrei Chabes*

Department of Medical Biochemistry and Biophysics, Umeå University, SE 901 87 Umeå, Sweden

*To whom correspondence should be addressed. Tel: +46 90 786 5937; Fax: +46 90 786 9795; Email: andrei.chabes{at}medchem.umu.se

Correspondence may also be addressed to Erik Johansson. Tel: +46 90 786 6638; Fax: +46 90 786 9795; Email: erik.johansson{at}medchem.umu.se

Received July 21, 2008. Revised August 14, 2008. Accepted August 14, 2008.

The enzyme ribonucleotide reductase, responsible for the synthesis of deoxyribonucleotides (dNTP), is upregulated in response to DNA damage in all organisms. In Saccharomyces cerevisiae, dNTP concentration increases ~6- to 8-fold in response to DNA damage. This concentration increase is associated with improved tolerance of DNA damage, suggesting that translesion DNA synthesis is more efficient at elevated dNTP concentration. Here we show that in a yeast strain with all specialized translesion DNA polymerases deleted, 4-nitroquinoline oxide (4-NQO) treatment increases mutation frequency ~3-fold, and that an increase in dNTP concentration significantly improves the tolerance of this strain to 4-NQO induced damage. In vitro, under single-hit conditions, the replicative DNA polymerase {varepsilon} does not bypass 7,8-dihydro-8-oxoguanine lesion (8-oxoG, one of the lesions produced by 4-NQO) at S-phase dNTP concentration, but does bypass the same lesion with 19–27% efficiency at DNA-damage-state dNTP concentration. The nucleotide inserted opposite 8-oxoG is dATP. We propose that during DNA damage in S. cerevisiae increased dNTP concentration allows replicative DNA polymerases to bypass certain DNA lesions.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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