Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response

Morin, Isabelle, Ngo, Hien Ping, Greenall, Amanda, Zubko, Mikhajlo K, Morrice, Nick and Lydall, David 2008. Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response. The EMBO Journal 27 (18) , pp. 2400-2410. 10.1038/emboj.2008.171

PDF - Published Version Available under License Creative Commons Attribution. Download (309kB)

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	EMBO Press
ISSN:	0261-4189
Date of First Compliant Deposit:	11 April 2023
Date of Acceptance:	30 July 2008
Last Modified:	11 Jun 2023 19:40
URI:	https://orca.cardiff.ac.uk/id/eprint/158409

Citation Data

Cited 129 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item