Journal
MOLECULAR CELL
Volume 57, Issue 6, Pages 1124-1132Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.01.043
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Funding
- National Institute of Health [R01-GM097272, R01-GM081425, R01-GM104424, R01-GM097358]
- American Cancer Society [RSG-11-146-01-DMC]
- Cornell Fleming Research Fellowship
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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.
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