ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage

被引:2413
作者
Matsuoka, Shuhei
Ballif, Bryan A.
Smogorzewska, Agata
McDonald, E. Robert, III
Hurov, Kristen E.
Luo, Ji
Bakalarski, Corey E.
Zhao, Zhenming
Solimini, Nicole
Lerenthal, Yaniv
Shiloh, Yosef
Gygi, Steven P.
Elledge, Stephen J. [1 ]
机构
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med,Howard HUghes Med Inst, Dept Genet, Boston, MA 02115 USA
[2] Harvard Univ, Brigham & Womens Hosp, Sch Med,Howard HUghes Med Inst, Ctr Genet & Genom, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Taplin Biol Mass Spectrometry Facil, Boston, MA 02115 USA
[5] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02214 USA
[6] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel
关键词
D O I
10.1126/science.1140321
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM ( ataxia telangiectasia mutated) and ATR ( ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this data set indicated that this list is highly enriched for proteins involved in the DDR. This set of proteins is highly interconnected, and we identified a large number of protein modules and networks not previously linked to the DDR. This database paints a much broader landscape for the DDR than was previously appreciated and opens new avenues of investigation into the responses to DNA damage in mammals.
引用
收藏
页码:1160 / 1166
页数:7
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