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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Journal ArticleDOI
Expression of Tra2β in Cancer Cells as a Potential Contributory Factor to Neoplasia and Metastasis
Andrew Best,Caroline Dagliesh,Ingrid Ehrmann,Mahsa Kheirollahi-Kouhestani,Alison Tyson-Capper,David J. Elliott +5 more
TL;DR: Evidence is reviewed that upregulation of the SR-related Tra2β protein might have a similar role in cancer cells, where they affect metastasis, proliferation, and cell survival.
Book ChapterDOI
Exploiting synthetic lethal interactions between DNA damage signaling, checkpoint control, and p53 for targeted cancer therapy.
TL;DR: The concept of synthetic lethality with a focus on p53, a commonly lost tumor suppressor gene, in the context of DNA damage signaling is discussed, with several recent examples in which this concept was successfully applied to target tumor cells in culture or in mouse models, as well as in human cancer patients.
Journal ArticleDOI
Germline BAP1 mutations and tumor susceptibility.
TL;DR: Two new studies describe germline mutations in BAP1 in putatively dissimilar cancer-related syndromes and the spectrum of neoplasms associated with these germ line mutations suggest that BAP 1 has an important tumor suppressor function in multiple tissues.
Journal ArticleDOI
A gemcitabine sensitivity screen identifies a role for NEK9 in the replication stress response
Scott C. Smith,Aleksandra V. Petrova,Matthew Z. Madden,Hongyan Wang,Yunfeng Pan,Matthew D. Warren,Claire W. Hardy,Dong Liang,Elaine A. Liu,M. Hope Robinson,Soumon Rudra,Jie Wang,Shahrzad Ehdaivand,Mylin A. Torres,Ya Wang,David S. Yu +15 more
TL;DR: NIMA (never in mitosis gene A)-related kinase 9 (NEK9) is a critical component of the RSR that promotes CHK1 activity, maintaining genome integrity following challenges to DNA replication.
Journal ArticleDOI
The Menin Tumor Suppressor Protein Is Phosphorylated in Response to DNA Damage
TL;DR: The findings suggest that the menin tumor suppressor protein undergoes DNA damage induced phosphorylation and participates in the DNA damage transcriptional response.
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.