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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Research data supporting "Systematic E2 screening reveals a UBE2D–RNF138–CtIP axis promoting DNA repair"
Christine K. Schmidt,Yaron Galanty,Matylda Sczaniecka-Clift,Julia Coates,Satpal Jhujh,Mukerrem Demir,Matthew Cornwell,Petra Beli,Stephen P. Jackson +8 more
TL;DR: In this paper, a complete set of graphs for gammaH2AX, 53BP1 and ubiquitin (FK2 antibody) foci/cell kinetics in response to ionising radiation (IR)- and mock-treated human U2OS cells treated with siRNAs targeting U2s (screening module 1; refers to Fig. 1).
Journal ArticleDOI
Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia.
Reena Prity Murmu,Reena Prity Murmu,Reena Prity Murmu,Elodie Martin,Elodie Martin,Elodie Martin,Agnès Rastetter,Agnès Rastetter,Agnès Rastetter,Typhaine Esteves,Typhaine Esteves,Typhaine Esteves,Marie-Paule Muriel,Marie-Paule Muriel,Marie-Paule Muriel,Khalid Hamid El Hachimi,Paola S. Denora,Aurélien Dauphin,Aurélien Dauphin,Aurélien Dauphin,José Carlos Fernandez,José Carlos Fernandez,José Carlos Fernandez,Charles Duyckaerts,Charles Duyckaerts,Charles Duyckaerts,Alexis Brice,Frédéric Darios,Frédéric Darios,Frédéric Darios,Giovanni Stevanin +30 more
TL;DR: This first study of the endogenous expression of spatacsin and spastizin shows similarities in their expression patterns that could account for their overlapping clinical phenotypes and involvement in a common protein complex.
Journal ArticleDOI
New insights into the roles of ATM and DNA-PKcs in the cellular response to oxidative stress
TL;DR: The growing understanding of the involvement of ATM, DNA-PKcs, and ATR in the oxidative stress response will offer new possibilities for the treatment of ROS-related diseases.
Journal ArticleDOI
Human single-stranded DNA binding proteins are essential for maintaining genomic stability.
TL;DR: A subset of single-stranded DNA binding proteins involved in the direct maintenance of genomic stability are discussed, an important cellular process in the conservation of cellular viability and prevention of malignant transformation.
Journal ArticleDOI
A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis.
Abdol Hossein Rezaeian,Abdol Hossein Rezaeian,Chien Feng Li,Ching Yuan Wu,Xian Zhang,Xian Zhang,Jorge Delacerda,M. James You,M. James You,Fei Han,Fei Han,Zhen Cai,Zhen Cai,Yun Seong Jeong,Yun Seong Jeong,Guoxiang Jin,Guoxiang Jin,Liem Phan,Ping Chieh Chou,Ping Chieh Chou,Mong Hong Lee,Mong Hong Lee,Mien Chie Hung,Mien Chie Hung,Mien Chie Hung,Dos D. Sarbassov,Dos D. Sarbassov,Hui Kuan Lin +27 more
TL;DR: TRAF6 and H2AX overexpression and γH2AX-mediated HIF1α enrichment in the nucleus of cancer cells lead to overactivation of Hif1α-driven tumorigenesis, glycolysis and metastasis, and the findings suggest that TRAF6-mediated mono-ubiquitylation and subsequent phosphorylation of H2 AX may serve as potential means for cancer diagnosis and therapy.
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.