Matsuoka Shuhei, Ballif Bryan A, Smogorzewska Agata, McDonald E Robert, Hurov Kristen E, Luo Ji, Bakalarski Corey E, Zhao Zhenming, Solimini Nicole, Lerenthal Yaniv, Shiloh Yosef, Gygi Steven P, Elledge Stephen J
Department of Genetics and Center for Genetics and Genomics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Science. 2007 May 25;316(5828):1160-6. doi: 10.1126/science.1140321.
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.
细胞对DNA损伤的反应由多种蛋白激酶介导，包括ATM（共济失调毛细血管扩张症突变基因）和ATR（ATM与Rad3相关蛋白）。该信号转导通路的大致轮廓已为人所知，但对于DNA损伤反应（DDR）的生理范围却知之甚少。我们对在ATM和ATR识别的共有位点上因DNA损伤而发生磷酸化的蛋白质进行了大规模蛋白质组学分析，鉴定出900多个受调控的磷酸化位点，涉及700多种蛋白质。对该数据集的一个子集进行功能分析表明，该列表中参与DDR的蛋白质高度富集。这组蛋白质之间高度相互连接，我们还鉴定出大量以前未与DDR相关联的蛋白质模块和网络。该数据库描绘出的DDR图景比以往所认识的要广阔得多，并为研究哺乳动物对DNA损伤的反应开辟了新的途径。
