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
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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
Cytoplasmic ATM protein kinase: an emerging therapeutic target for diabetes, cancer and neuronal degeneration.
TL;DR: The potential for cytoplasmic ATM protein kinase to be an emerging therapeutic target for treating diabetes, cancer and neuronal degeneration is discussed.
Journal ArticleDOI
DNA Repair Biomarker Profiling of Head and Neck Cancer: Ku80 Expression Predicts Locoregional Failure and Death following Radiotherapy
Benjamin J. Moeller,John S. Yordy,Michelle D. Williams,Uma Giri,Uma Raju,David Molkentine,Lauren Averett Byers,John V. Heymach,Michael D. Story,J. Jack Lee,Erich M. Sturgis,Randal S. Weber,Adam S. Garden,K. Kian Ang,David L. Schwartz +14 more
TL;DR: Ku80 overexpression is a common feature of HNSCC, and is a candidate DNA repair-related biomarker for radiation treatment failure and death, particularly in patients with high-risk HPV-negative disease.
Journal ArticleDOI
ATM and SIRT6/SNF2H Mediate Transient H2AX Stabilization When DSBs Form by Blocking HUWE1 to Allow Efficient γH2AX Foci Formation.
Yuko Atsumi,Yusuke Minakawa,Masaya Ono,Sachiko Dobashi,Keitaro Shinohe,Akira Shinohara,Shunichi Takeda,Masatoshi Takagi,Nobuhiko Takamatsu,Hitoshi Nakagama,Hirobumi Teraoka,Ken ichi Yoshioka +11 more
TL;DR: It is shown that H2AX is rapidly stabilized in response to DSBs to efficiently generate γH2AX foci, and a pathway controlled by ATM, SIRT6, and SNF2H to block HUWE1 is revealed, which stabilizes H2 AX and induces its incorporation into chromatin only when cells are damaged.
Journal ArticleDOI
MRE11 UFMylation promotes ATM activation.
Zhifeng Wang,Zhifeng Wang,Yamin Gong,Yamin Gong,Bin Peng,Ruifeng Shi,Ruifeng Shi,Dan Fan,Hongchang Zhao,Min Zhu,Haoxing Zhang,Zhenkun Lou,Jianwei Zhou,Wei-Guo Zhu,Yu-Sheng Cong,Xingzhi Xu,Xingzhi Xu +16 more
TL;DR: Taken together, MRE11 UFMylation promotes ATM activation, DSB repair and genome stability, and potentially serves as a therapeutic target.
Journal ArticleDOI
DNA replication stress and cancer chemotherapy.
Hiroyuki Kitao,Makoto Iimori,Yuki Kataoka,Takeshi Wakasa,Eriko Tokunaga,Hiroshi Saeki,Eiji Oki,Yoshihiko Maehara +7 more
TL;DR: In this review, the current understanding of DRS in tumors is introduced and the underlying mechanism of cancer therapy from the aspect of D RS is discussed.
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.