Phosphoproteomics reveals distinct modes of Mec1/ATR signaling during DNA replication.
The Mec1/Tel1 kinases (human ATR/ATM) play numerous roles in the DNA replication stress response. Despite the multi-functionality of these kinases, studies of their in vivo action have mostly relied on a few well-established substrates. Here we employed a combined genetic-phosphoproteomic approach to monitor Mec1/Tel1 signaling in a systematic, unbiased, and quantitative manner. ... Unexpectedly, we find that Mec1 is highly active during normal DNA replication, at levels comparable or higher than Mec1's activation state induced by replication stress. This "replication-correlated" mode of Mec1 action requires the 9-1-1 clamp and the Dna2 lagging-strand factor and is distinguishable from Mec1's action in activating the downstream kinase Rad53. We propose that Mec1/ATR performs key functions during ongoing DNA synthesis that are distinct from their canonical checkpoint role during replication stress.
Mesh Terms:
Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Checkpoint Kinase 2, DNA Replication, Humans, Intracellular Signaling Peptides and Proteins, Phosphoproteins, Phosphorylation, Protein-Serine-Threonine Kinases, Proteomics, Proto-Oncogene Proteins c-ets, Repressor Proteins, Saccharomyces cerevisiae Proteins, Signal Transduction
Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Checkpoint Kinase 2, DNA Replication, Humans, Intracellular Signaling Peptides and Proteins, Phosphoproteins, Phosphorylation, Protein-Serine-Threonine Kinases, Proteomics, Proto-Oncogene Proteins c-ets, Repressor Proteins, Saccharomyces cerevisiae Proteins, Signal Transduction
Mol. Cell
Date: Mar. 19, 2015
PubMed ID: 25752575
View in: Pubmed Google Scholar
Download Curated Data For This Publication
205987
Switch View:
- Interactions 4