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
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Efficient Pre-mRNA Cleavage Prevents Replication-Stress-Associated Genome Instability
Federico Teloni,Jone Michelena,Aleksandra Lezaja,Sinan Kilic,Christina Ambrosi,Shruti Menon,Jana Dobrovolna,Ralph Imhof,Pavel Janscak,Tuncay Baubec,Matthias Altmeyer +10 more
TL;DR: It is shown that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function, and that inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe.
Journal ArticleDOI
Motif-specific sampling of phosphoproteomes.
Cristian I. Ruse,Daniel B. McClatchy,Bingwen Lu,Daniel Cociorva,Akira Motoyama,Sung Kyu Park,John R. Yates +6 more
TL;DR: A methodology that linked phosphoproteome and proteome analysis based on Ba2+ binding properties of amino acids was described, which selected motif-specific phosphopeptides independent of the system under analysis.
Journal ArticleDOI
Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity
Conor J Howard,Victor Hanson-Smith,Kristopher J Kennedy,Chad J. Miller,Hua J.ane Lou,Alexander D. Johnson,Benjamin E. Turk,Liam J. Holt +7 more
TL;DR: In this paper, the authors studied the CMGC protein kinases using ancestral reconstruction and found that cyclin dependent kinases and mitogen activated protein kinase (MAPKs) require proline at the +1 position of their substrates, while Ime2 prefers arginine.
Journal ArticleDOI
Benchmarking substrate-based kinase activity inference using phosphoproteomic data
Claudia Hernandez-Armenta,David Ochoa,Emanuel Gonçalves,Julio Saez-Rodriguez,Julio Saez-Rodriguez,Pedro Beltrao +5 more
TL;DR: It is proposed that changes in phosphorylation of kinase target sites can be used to infer when a kinase activity is under regulation, but these approaches have not yet been benchmarked due to a lack of appropriate benchmarking strategies.
Journal ArticleDOI
Characterization of the effects of cisplatin and carboplatin on cell cycle progression and DNA damage response activation in DNA polymerase eta-deficient human cells.
Séverine Cruet-Hennequart,Sangamitra Villalan,Agnieszka Kaczmarczyk,Elaine O'Meara,Anna M. Sokol,Michael P. Carty +5 more
TL;DR: It is directly demonstrated, using dual-labeling flow cytometry, that damage-induced phosphorylation of RPA2 on serine4/serine8 occurs primarily in the S and G2 phases of the cell cycle, and that the timing of R PA2 phosphorylated proteins can be modulated by inhibition of the checkpoint kinase Chk1.
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.