Journal ArticleDOI
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage
Shuhei Matsuoka,Bryan A. Ballif,Agata Smogorzewska,Agata Smogorzewska,E. Robert McDonald,Kristen E. Hurov,Ji Luo,Corey E. Bakalarski,Zhenming Zhao,Nicole L. Solimini,Yaniv Lerenthal,Yosef Shiloh,Steven P. Gygi,Stephen J. Elledge +13 more
TLDR
A large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR is performed and more than 900 regulated phosphorylation sites encompassing over 700 proteins are identified.Abstract:
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.read more
Citations
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Journal ArticleDOI
Proteomics and phosphoproteomics for the mapping of cellular signalling networks
TL;DR: Recent advances in proteomics are reviewed with focus on cellular signalling pathways as well as genetics‐based and biochemistry‐based methods such as two‐dimensional gel electrophoresis, quantitative proteochemistry, interaction proteomics, and phosphoproteomics.
Book ChapterDOI
Modeling signaling networks using high-throughput phospho-proteomics.
TL;DR: This chapter reviews recent developments in both data acquisition and computational analysis of signaling networks, and describes two approaches, antibody based technologies and mass spectrometry (MS), along with their main features and limitations.
Journal ArticleDOI
CENP-A chromatin disassembly in stressed and senescent murine cells
TL;DR: Together, these findings bring out cooperation between DDR effectors and loss of centromere integrity as a safeguard mechanism to prevent genomic instability in context of persistent DNA damage signalling.
Journal ArticleDOI
Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer
Yunhua Liu,Yunhua Liu,Yunhua Liu,Jiangsheng Xu,Jiangsheng Xu,Hyun Ho Choi,Cecil Han,Yuanzhang Fang,Yuanzhang Fang,Yujing Li,Yujing Li,Kevin Van der Jeught,Kevin Van der Jeught,Hanchen Xu,Hanchen Xu,Lu Zhang,Lu Zhang,Lu Zhang,Michael Frieden,Lifei Wang,Haniyeh Eyvani,Yifan Sun,Gang Zhao,Yuntian Zhang,Yuntian Zhang,Sheng Liu,Jun Wan,Cheng Huang,Guang Ji,Xiongbin Lu,Xiongbin Lu,Xiaoming He,Xinna Zhang +32 more
TL;DR: In this paper, pH-sensitive nanoparticles were developed for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+breast tumors, leading to a profound reduction of tumor growth.
Journal ArticleDOI
Requirement of MTA1 in ATR-mediated DNA damage checkpoint function
TL;DR: It is reported that UV radiation stabilizes MTA1 in an ATR-dependent manner and increases MTA1 binding to ATR and the noted abrogation of the DNA damage checkpoint in the MTA1-depleted cells may be a consequence of dysregulation of the expression of these two pathways.
References
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Journal ArticleDOI
The DNA damage response: putting checkpoints in perspective
TL;DR: The inability to repair DNA damage properly in mammals leads to various disorders and enhanced rates of tumour development, and this work has shown that direct activation of DNA repair networks is needed to correct this problem.
Journal ArticleDOI
Cell-cycle checkpoints and cancer
Michael B. Kastan,Jiri Bartek +1 more
TL;DR: All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation, and how cells respond to DNA damage are critical determinants of whether that individual will develop cancer.
Journal ArticleDOI
DNA damage-induced activation of p53 by the checkpoint kinase Chk2.
Atsushi Hirao,Young-Yun Kong,Shuhei Matsuoka,Andrew Wakeham,Jürgen Ruland,Hiroki Yoshida,Dou Liu,Stephen J. Elledge,Tak W. Mak +8 more
TL;DR: Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding, and provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage.
Journal ArticleDOI
Immunoaffinity profiling of tyrosine phosphorylation in cancer cells
John Rush,Albrecht Moritz,Kimberly Lee,Ailan Guo,Valerie Goss,Erik Spek,Hui Zhang,Hui Zhang,Hui Zhang,Xiang-ming Zha,Xiang-ming Zha,Xiang-ming Zha,Roberto D. Polakiewicz,Michael J. Comb +13 more
TL;DR: Applying this approach to several cell systems, including cancer cell lines, shows it can be used to identify activated protein kinases and their phosphorylated substrates without prior knowledge of the signaling networks that are activated, a first step in profiling normal and oncogenic signaling networks.
Journal Article
Global Analysis of Protein Phosphorylation in Yeast
Jason Ptacek,Geeta Devgan,Gregory A. Michaud,Heng Zhu,Xiaowei Zhu,Joseph Fasolo,Hong Guo,Ghil Jona,Ashton Breitkreutz,Richelle Sopko,Rhonda R. McCartney,Martin C. Schmidt,Najma Rachidi,Soo-Jung Lee,Angie S. Mah,Lihao Meng,Michael J. R. Stark,David F. Stern,Claudio De Virgilio,Mike Tyers,Brenda J. Andrews,Mark Gerstein,Barry Schweitzer,Paul F. Predki,Michael Snyder +24 more
TL;DR: The in vitro substrates recognized by most yeast protein kinases are described, with the use of proteome chip technology, and these results will provide insights into the mechanisms and roles of protein phosphorylation in many eukaryotes.