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Pre-activation of the genome integrity checkpoint increases DNA damage tolerance
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).ORCID iD: 0000-0003-1708-8259
2013 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 41, no 22, 10371-10378 p.Article in journal (Refereed) Published
Abstract [en]

The genome integrity checkpoint is a conserved signaling pathway that is regulated in yeast by the Mec1 (homologous to human ATR) and Rad53 (homologous to human Chk1) kinases. The pathway coordinates a multifaceted response that allows cells to cope with DNA damage and DNA replication stress. The full activation of the checkpoint blocks origin firing, stabilizes replication forks, activates DNA repair proteins and may lead to senescence or apoptosisin higher eukaryotes. We have recently demonstrated that endogenous replication stress can activate the genome integrity checkpoint in budding yeast at a low level that does not go so far as to interfere with cell cycle progression, but it does activate DNA damage-inducible proteins. Here we demonstrate that the low level pre-activation of the checkpoint, either by endogenous replication stress or by the nucleotide-depleting drug hydroxyurea, can increase damage tolerance to multiple DNA-damaging agents. These results may provide new strategies for using the checkpoint to protect normal cells from genotoxic stress.

Place, publisher, year, edition, pages
Oxford University Press, 2013. Vol. 41, no 22, 10371-10378 p.
National Category
Basic Medicine
URN: urn:nbn:se:umu:diva-80658DOI: 10.1093/nar/gkt820PubMedID: 24049076OAI: diva2:650677
Available from: 2013-09-23 Created: 2013-09-23 Last updated: 2014-06-12Bibliographically approved

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Tsaponina, OlgaChabes, Andrei
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