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Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response

Lookup NU author(s): Dr Isabelle Morin, Dr Greg Ngo, Dr Amanda Greenall, Dr Mikhajlo Zubko, Professor David Lydall

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Abstract

Exo1 is a nuclease involved in mismatch repair, DSB repair, stalled replication fork processing and in the DNA damage response triggered by dysfunctional telomeres. In budding yeast and mice, Exo1 creates single-stranded DNA (ssDNA) at uncapped telomeres. This ssDNA accumulation activates the checkpoint response resulting in cell cycle arrest. Here, we demonstrate that Exo1 is phosphorylated when telomeres are uncapped in cdc13-1 and yku70Δ yeast cells, and in response to the induction of DNA damage. After telomere uncapping, Exo1 phosphorylation depends on components of the checkpoint machinery such as Rad24, Rad17, Rad9, Rad53 and Mec1, but is largely independent of Chk1, Tel1 and Dun1. Serines S372, S567, S587 and S692 of Exo1 were identified as targets for phosphorylation. Furthermore, mutation of these Exo1 residues altered the DNA damage response to uncapped telomeres and camptothecin treatment, in a manner that suggests Exo1 phosphorylation inhibits its activity. We propose that Rad53-dependent Exo1 phosphorylation is involved in a negative feedback loop to limit ssDNA accumulation and DNA damage checkpoint activation. ©2008 European Molecular Biology Organization.

Publication metadata

Author(s): Morin I, Ngo H-P, Greenall A, Zubko MK, Morrice N, Lydall D

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2008

Volume: 27

Issue: 18

Pages: 2400-2410

Date deposited: 08/02/2010

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/emboj.2008.171

DOI: 10.1038/emboj.2008.171

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