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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Hsp90 phosphorylation, Wee1 and the cell cycle
TL;DR: Additional data is presented demonstrating that tyrosine phosphorylation of Hsp90 by Wee1Swe1 is important for Wee1 Swe1 association with Hsp 90 and for Wee 1Swe1 stability, and the importance of HSp90 phosphorylated for proper cell cycle regulation.
Journal ArticleDOI
RNF20–RNF40: A ubiquitin-driven link between gene expression and the DNA damage response
TL;DR: New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein.
Journal ArticleDOI
ATR maintains select progenitors during nervous system development
Youngsoo Lee,Erin R.P. Shull,Erin R.P. Shull,Pierre Olivier Frappart,Sachin Katyal,Vanessa Enriquez-Rios,Vanessa Enriquez-Rios,Jingfeng Zhao,Helen R. Russell,Eric J. Brown,Peter J. McKinnon,Peter J. McKinnon +11 more
TL;DR: The data indicate that ATR functions to monitor genomic integrity in a selective spatiotemporal manner during neurogenesis, supporting non‐overlapping physiological roles for these related DNA damage‐response kinases in the brain.
Journal ArticleDOI
Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2.
Martin R. Higgs,Koichi Sato,John J. Reynolds,Shabana Begum,Rachel Bayley,Amalia Goula,Audrey Vernet,Karissa L. Paquin,David G. Skalnik,Wataru Kobayashi,Minoru Takata,Niall G. Howlett,Hitoshi Kurumizaka,Hiroshi Kimura,Grant S. Stewart +14 more
TL;DR: It is reported that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection.
Journal ArticleDOI
Nuclear phosphorylated Dicer processes double-stranded RNA in response to DNA damage.
Kaspar Burger,Margarita Schlackow,Martin Potts,Svenja Hester,Shabaz Mohammed,Monika Gullerova +5 more
TL;DR: It is shown that human Dicer is phosphorylated in the platform–Piwi/Argonaute/Zwille–connector helix cassette (S1016) upon induction of DNA damage and turnover of damage-induced nuclear, double-stranded RNA requires additional phosphorylation of carboxy-terminal Dicer residues.
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.