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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A Genetic Screen Identifies FAN1, a Fanconi Anemia-Associated Nuclease Necessary for DNA Interstrand Crosslink Repair
Agata Smogorzewska,Agata Smogorzewska,Agata Smogorzewska,Rohini Desetty,Takamune T. Saito,Michael R. Schlabach,Francis P. Lach,Mathew E. Sowa,Alan B. Clark,Thomas A. Kunkel,J. Wade Harper,Monica P. Colaiácovo,Stephen J. Elledge +12 more
TL;DR: It is proposed that FAN1 is a repair nuclease that is recruited to sites of crosslink damage in part through binding the ubiquitinated ID complex through its UBZ domain.
Journal ArticleDOI
Regulation of Homologous Recombination by RNF20-Dependent H2B Ubiquitination
Kyosuke Nakamura,Akihiro Kato,Junya Kobayashi,Hiromi Yanagihara,Shuichi Sakamoto,Douglas V. N. P. Oliveira,Mikio Shimada,Hiroshi Tauchi,Hidekazu Suzuki,Satoshi Tashiro,Lee Zou,Kenshi Komatsu +11 more
TL;DR: The RNF20-mediated H2B ubiquitination at DSBs plays a critical role in HRR through chromatin remodeling and can be partially bypassed by forced chromatin relaxation.
Journal ArticleDOI
ATM Mutations in Cancer: Therapeutic Implications
TL;DR: Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors, and may be exploited by existing or emerging targeted therapies that produce synthetic lethal states.
Journal ArticleDOI
Nonsense-mediated mRNA decay — Mechanisms of substrate mRNA recognition and degradation in mammalian cells☆
TL;DR: translation termination in a messenger ribonucleoprotein particle (mRNP) environment lacking necessary factors for proper translation termination emerges as a key determinant for subjecting an mRNA to NMD, and recent structural and mechanistic insight into translation termination is reviewed.
Journal ArticleDOI
Screen for DNA‐damage‐responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells
TL;DR: Though most histone modifications do not change appreciably after genotoxic stress, H3K9Ac and H3k56Ac are reduced in response to DNA damage in human cells, and it is shown that the histone acetyl‐transferase GCN5/KAT2A acetylates H 3K56 in vitro and in vivo.
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.