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:Â
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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Post-translational modifications in signal integration
TL;DR: The common principles of post-translational modifications and their importance in signal integration underlying epidermal growth factor receptor signaling and endocytosis, DNA-damage responses and immunity are reviewed.
Journal ArticleDOI
Mass spectrometry for proteomics
TL;DR: Although bottom-up proteomics remains the workhorse for proteomic analysis, middle-down and top-down strategies should allow more complete characterization of protein isoforms and post-translational modifications.
Journal ArticleDOI
Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins.
TL;DR: Now that the gene that is defective in the thirteenth and last assigned FA complementation group (FANCI) has been identified, what is known about FA proteins and their interactive network, and what remains to be discovered are discussed.
Journal ArticleDOI
ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS
Angela Alexander,Sheng Li Cai,Jinhee Kim,Adrian Nanez,Mustafa Sahin,Kirsteen H. Maclean,Ken Inoki,Kun-Liang Guan,Jianjun Shen,Maria D. Person,Donna F. Kusewitt,Donna F. Kusewitt,Gordon B. Mills,Michael B. Kastan,Cheryl L. Walker,Cheryl L. Walker +15 more
TL;DR: A cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy is identified, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.
Journal ArticleDOI
ATM-Dependent Chromatin Changes Silence Transcription In cis to DNA Double-Strand Breaks
Niraj M. Shanbhag,Ilona U. Rafalska-Metcalf,Carlo Balane-Bolivar,Susan M. Janicki,Roger A. Greenberg +4 more
TL;DR: Using a novel reporter that allows for visualization of repair protein recruitment and local transcription in single cells, an ATM-dependent transcriptional silencing program in cis to DSBs is described, giving insight into the role of posttranslational modifications in mediating crosstalk between diverse processes occurring on chromatin.
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.