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PLoS Genet. 2011 Apr;7(4):e1001367. doi: 10.1371/journal.pgen.1001367. Epub 2011 Apr 14.

14-3-3 Proteins regulate exonuclease 1-dependent processing of stalled replication forks.

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  • 1Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.

Abstract

Replication fork integrity, which is essential for the maintenance of genome stability, is monitored by checkpoint-mediated phosphorylation events. 14-3-3 proteins are able to bind phosphorylated proteins and were shown to play an undefined role under DNA replication stress. Exonuclease 1 (Exo1) processes stalled replication forks in checkpoint-defective yeast cells. We now identify 14-3-3 proteins as in vivo interaction partners of Exo1, both in yeast and mammalian cells. Yeast 14-3-3-deficient cells fail to induce Mec1-dependent Exo1 hyperphosphorylation and accumulate Exo1-dependent ssDNA gaps at stalled forks, as revealed by electron microscopy. This leads to persistent checkpoint activation and exacerbated recovery defects. Moreover, using DNA bi-dimensional electrophoresis, we show that 14-3-3 proteins promote fork progression under limiting nucleotide concentrations. We propose that 14-3-3 proteins assist in controlling the phosphorylation status of Exo1 and additional unknown targets, promoting fork progression, stability, and restart in response to DNA replication stress.

PMID:
21533173
[PubMed - indexed for MEDLINE]
PMCID:
PMC3077382
Free PMC Article

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