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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MicroRNAs and DNA damage response: implications for cancer therapy.
Yemin Wang,Toshiyasu Taniguchi +1 more
TL;DR: Recent findings related to the emerging roles of miRNAs in regulating DDR and DNA repair are summarized and their potential in cancer therapy is discussed.
Journal ArticleDOI
DNA-PK phosphorylation of RPA32 Ser4/Ser8 regulates replication stress checkpoint activation, fork restart, homologous recombination and mitotic catastrophe.
Amanda K. Ashley,Meena Shrivastav,Jingyi Nie,Courtney Amerin,Kyle Troksa,Jason G. Glanzer,Shengqin Liu,Stephen O. Opiyo,Diana D. Dimitrova,Phuong Le,Brock J. Sishc,Susan M. Bailey,Gregory G. Oakley,Jac A. Nickoloff,Jac A. Nickoloff +14 more
TL;DR: It is shown that DNA-PK and ATR signaling through RPA32 plays a critical role in promoting genome stability and cell survival in response to replication stress, and that hyper-recombination in these mutants is ATM-dependent, but the other defects are ATM-independent.
Journal ArticleDOI
Mislocalization of the MRN complex prevents ATR signaling during adenovirus infection
Christian T. Carson,Christian T. Carson,Nicole I. Orazio,Nicole I. Orazio,Darwin V. Lee,Junghae Suh,Simon Bekker-Jensen,Felipe D. Araujo,Seema S. Lakdawala,Seema S. Lakdawala,Caroline E. Lilley,Jiri Bartek,Jiri Lukas,Matthew D. Weitzman +13 more
TL;DR: It is found that ATM and ATR signaling are not dependent on each other during infection, and it is proposed that immobilization of the MRN damage sensor by E4orf3 protein prevents recognition of viral genomes and blocks detrimental aspects of checkpoint signaling during virus infection.
Journal ArticleDOI
SHLD2/FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice
Steven Findlay,Steven Findlay,John E. Heath,John E. Heath,Vincent M Luo,Vincent M Luo,Abba Malina,Abba Malina,Théo Morin,Yan Coulombe,Billel Djerir,Zhigang Li,Arash Samiei,Arash Samiei,Estelle Simo-Cheyou,Estelle Simo-Cheyou,Martin Karam,Halil Bagci,Dolev Rahat,Damien Grapton,Elise G Lavoie,Christian Dove,Christian Dove,Husam Khaled,Husam Khaled,Hellen Kuasne,Koren K. Mann,Koren K. Mann,Kathleen Oros Klein,Celia M. T. Greenwood,Yuval Tabach,Morag Park,Jean-François Côté,Jean-Yves Masson,Alexandre Maréchal,Alexandre Orthwein +35 more
TL;DR: Together, these results establish SHLD2 as a novel effector of REV7 in controlling the decision‐making process during DSB repair in NHEJ‐mediated DNA repair and compromises antibody diversification by class switch recombination (CSR) in B cells.
Journal ArticleDOI
Charting the Landscape of Tandem BRCT Domain–Mediated Protein Interactions
Nicholas T. Woods,Rafael D. Mesquita,Michael Sweet,Marcelo A. Carvalho,Xueli Li,Yun Liu,Huey Nguyen,C. Eric Thomas,Edwin S. Iversen,Sylvia M. Marsillac,Rachel Karchin,John M. Koomen,Alvaro N.A. Monteiro +12 more
TL;DR: Bioinformatics analysis of the BRCT protein-protein interaction network revealed biological processes and protein complexes that integrate the DDR with cell cycle regulation and transcription and signaling subnetworks that may aid in understanding the involvement of tBRCT in disease and DNA repair.
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.