Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response.
Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response.
复制标题
DOI：
10.1038/emboj.2008.171
复制
发表时间：
2008-09-17
期刊：
影响因子：
11.4
通讯作者：
Lydall, David
中科院分区：
文献类型：
--
作者：
Morin, Isabelle;Ngo, Hien-Ping;Greenall, Amanda;Zubko, Mikhajlo K.;Morrice, Nick;Lydall, David
Exo1是一种核酸酶，参与错配修复、DSB修复、停滞复制叉加工和功能失调端粒引发的DNA损伤反应。在出芽酵母和小鼠中，Exo1在未封顶的端粒上产生单链DNA （ssDNA）。这种ssDNA的积累激活了检查点反应，导致细胞周期停滞。在这里，我们证明了当cdc13-1和yku70Δ酵母细胞的端粒被解开时，Exo1被磷酸化，并对DNA损伤的诱导做出反应。端粒脱帽后，Exo1磷酸化依赖于检查点机制的组成部分，如Rad24、Rad17、Rad9、Rad53和Mec1，但在很大程度上独立于Chk1、Tel1和Dun1。Exo1的S372、S567、S587和S692丝氨酸被鉴定为磷酸化的靶点。此外，这些Exo1残基的突变改变了DNA对无帽端粒和喜树碱治疗的损伤反应，在某种程度上表明Exo1磷酸化抑制其活性。我们认为依赖rad53的Exo1磷酸化参与了一个负反馈回路，以限制ssDNA的积累和DNA损伤检查点的激活。
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.
登录
查看更多内容
影响因子：
4.8
作者：
Chen, Sheng-hong;Smolka, Marcus B.;Zhou, Huilin
通讯作者：
Zhou, Huilin
影响因子：
64.8
作者：
JOHNSTON, LH;NASMYTH, KA
通讯作者：
NASMYTH, KA
影响因子：
11.2
作者：
El-Shemerly, M;Janscak, P;Ferrari, S
通讯作者：
Ferrari, S
影响因子：
5.3
作者：
Fiorentini, P;Huang, KN;Symington, LS
通讯作者：
Symington, LS
影响因子：
5.3
作者：
FOIANI, M;MARINI, F;PLEVANI, P
通讯作者：
PLEVANI, P