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@article{Tannous:2021:10.1038/s41594-020-00522-0,
author = {Tannous, EA and Yates, LA and Zhang, X and Burgers, PM},
doi = {10.1038/s41594-020-00522-0},
journal = {Nature Structural and Molecular Biology},
pages = {50--61},
title = {Mechanism of auto-inhibition and activation of Mec1ATR checkpoint kinase},
url = {http://dx.doi.org/10.1038/s41594-020-00522-0},
volume = {28},
year = {2021}
}

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TY  - JOUR
AB  - In response to DNA damage or replication fork stalling, the basal activity of Mec1ATR is stimulated in a cell-cycle-dependent manner, leading to cell-cycle arrest and the promotion of DNA repair. Mec1ATR dysfunction leads to cell death in yeast and causes chromosome instability and embryonic lethality in mammals. Thus, ATR is a major target for cancer therapies in homologous recombination-deficient cancers. Here we identify a single mutation in Mec1, conserved in ATR, that results in constitutive activity. Using cryo-electron microscopy, we determine the structures of this constitutively active form (Mec1(F2244L)-Ddc2) at 2.8 Å and the wild type at 3.8 Å, both in complex with Mg2+-AMP-PNP. These structures yield a near-complete atomic model for Mec1-Ddc2 and uncover the molecular basis for low basal activity and the conformational changes required for activation. Combined with biochemical and genetic data, we discover key regulatory regions and propose a Mec1 activation mechanism.
AU  - Tannous,EA
AU  - Yates,LA
AU  - Zhang,X
AU  - Burgers,PM
DO  - 10.1038/s41594-020-00522-0
EP  - 61
PY  - 2021///
SN  - 1545-9985
SP  - 50
TI  - Mechanism of auto-inhibition and activation of Mec1ATR checkpoint kinase
T2  - Nature Structural and Molecular Biology
UR  - http://dx.doi.org/10.1038/s41594-020-00522-0
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33169019
UR  - http://hdl.handle.net/10044/1/84053
VL  - 28
ER  -

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