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A conserved Polϵ binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1
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García-Rodríguez, Luis J., De Piccoli, Giacomo, Marchesi, Vanessa, Jones, Richard C., Edmondson, Ricky D. and Labib, Karim (2015) A conserved Polϵ binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1. Nucleic Acids Research, 43 (18). pp. 8830-8838. doi:10.1093/nar/gkv799 ISSN 0305-1048.
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Official URL: http://dx.doi.org/10.1093/nar/gkv799
Abstract
Defects during chromosome replication in eukaryotes activate a signaling pathway called the S-phase checkpoint, which produces a multifaceted response that preserves genome integrity at stalled DNA replication forks. Work with budding yeast showed that the ‘alternative clamp loader’ known as Ctf18-RFC acts by an unknown mechanism to activate the checkpoint kinase Rad53, which then mediates much of the checkpoint response. Here we show that budding yeast Ctf18-RFC associates with DNA polymerase epsilon, via an evolutionarily conserved ‘Pol ϵ binding module’ in Ctf18-RFC that is produced by interaction of the carboxyl terminus of Ctf18 with the Ctf8 and Dcc1 subunits. Mutations at the end of Ctf18 disrupt the integrity of the Pol ϵ binding module and block the S-phase checkpoint pathway, downstream of the Mec1 kinase that is the budding yeast orthologue of mammalian ATR. Similar defects in checkpoint activation are produced by mutations that displace Pol ϵ from the replisome. These findings indicate that the association of Ctf18-RFC with Pol ϵ at defective replication forks is a key step in activation of the S-phase checkpoint.
Item Type: | Journal Article | ||||||
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Alternative Title: | |||||||
Subjects: | Q Science > QH Natural history Q Science > QR Microbiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Chromosome replication, DNA -- Synthesis, Saccharomyces cerevisiae, Yeast -- Genetics, Eukaryotic cells | ||||||
Journal or Publication Title: | Nucleic Acids Research | ||||||
Publisher: | Oxford University Press | ||||||
ISSN: | 0305-1048 | ||||||
Official Date: | 15 October 2015 | ||||||
Dates: |
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Volume: | 43 | ||||||
Number: | 18 | ||||||
Page Range: | pp. 8830-8838 | ||||||
DOI: | 10.1093/nar/gkv799 | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||
Date of first compliant deposit: | 19 January 2017 | ||||||
Date of first compliant Open Access: | 19 January 2017 | ||||||
Funder: | Cancer Research UK (CRUK), Medical Research Council (Canada) (MRC), Wellcome Trust (London, England) | ||||||
Grant number: | C44595/A16326 (CRUK), 97945/B/11/Z, 102943/Z/13/Z (Wellcome Trust) |
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