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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.
Original language | English |
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Pages (from-to) | 8830-8838 |
Journal | Nucleic Acids Research |
Volume | 43 |
Issue number | 18 |
Early online date | 6 Aug 2015 |
DOIs | |
Publication status | Published - 15 Oct 2015 |
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Dive into the research topics of 'A conserved Polϵ binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1'. Together they form a unique fingerprint.Projects
- 1 Finished
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Functional Dissection of the Eukaryotic Replisome (Senior Investigator Award)
Labib, K. (Investigator)
1/04/14 → 29/02/20
Project: Research