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
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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The Adherens Junction Protein Afadin Is an AKT Substrate that Regulates Breast Cancer Cell Migration
TL;DR: Phosphorylation of the adhesion protein Afadin by AKT downstream of the PI3K pathway, leads to redistribution of Afadin and controls cancer cell migration.
Journal ArticleDOI
RNF8-dependent and RNF8-independent Regulation of 53BP1 in Response to DNA Damage
Ryo Sakasai,Randal S. Tibbetts +1 more
TL;DR: The potential role of the proteasome in checkpoint activation and ATM/ATR signaling in response to UV light-induced DNA damage is examined and RNF8 ubiquitylation pathways are consistent with a model in which R NF8-independent pathways contribute to 53BP1 targeting and phosphorylation in responseto UV light and potentially other forms of DNA replication stress.
Journal ArticleDOI
COP9 signalosome function in the DDR
Ronny Hannß,Wolfgang Dubiel +1 more
TL;DR: Current knowledge on CSN function in DDR is reviewed to establish whether CSN controls the stability of DDR effectors such as p53 and p27 and thereby the DDR outcome.
Journal ArticleDOI
ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration.
Gururaj Rao Kidiyoor,Qingsen Li,Giulia Bastianello,Christopher Bruhn,Irene Giovannetti,Adhil Mohamood,Galina V. Beznoussenko,Alexandre A. Mironov,Matthew Raab,Matthieu Piel,Umberto Restuccia,Vittoria Matafora,Angela Bachi,Sara Barozzi,Dario Parazzoli,Emanuela Frittoli,Andrea Palamidessi,Tito Panciera,Stefano Piccolo,Giorgio Scita,Paolo Maiuri,Kristina M. Havas,Zhong-Wei Zhou,Zhong-Wei Zhou,Amit Kumar,Jiri Bartek,Zhao-Qi Wang,Zhao-Qi Wang,Marco Foiani +28 more
TL;DR: The findings indicate that ATR ensures mechanical coupling of the cytoskeleton to the nuclear envelope and accompanying regulation of envelope-chromosome association and the repertoire of ATR-regulated biological processes extends well beyond its canonical role in triggering biochemical implementation of the DNA damage response.
Journal ArticleDOI
How should we define STAT3 as an oncogene and as a potential target for therapy
TL;DR: The obligation to target a defined tumor type implies that future clinical trials should use a precise definition of STAT3 activation, which will allow tumors addicted to this oncogene to be identified correctly, leading to a strong rationale for patient stratification.
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.