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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mRNA Expression of BRCA1, PIAS1, and PIAS4 and Survival After Second-line Docetaxel in Advanced Gastric Cancer
Jia Wei,Carlota Costa,Yitao Ding,Zhengyun Zou,Lixia Yu,Jose Javier Sanchez,Xiaoping Qian,Hong Chen,Ana Giménez-Capitán,Fanqing Meng,Teresa Moran,Susana Benlloch,Miquel Taron,Rafael Rosell,Baorui Liu +14 more
TL;DR: Survition in patients receiving second-line docetaxel-based chemotherapy showed a similar trend with PIAS1 and PIAS4 mRNA expression levels, although the associations for PIas4 were not statistically significant.
Journal ArticleDOI
Mdmx promotes genomic instability independent of p53 and Mdm2.
TL;DR: A novel p53- and Mdm2-independent oncogenic function of Mdmx is revealed that provides new insight into the many cancers that overexpress MDMx and resulted in delayed DNA repair and increased genome instability and transformation independent of p53 and MDM2.
Journal ArticleDOI
Mechanisms of ATR-mediated checkpoint signalling.
TL;DR: Current progress in the understanding of the regulatory factors involved in the ATR-mediated checkpoint response, as well as resumption of cell cycle progression upon repair of the damage, are reviewed, thereby focussing on the mechanisms in mammalian cells.
Journal ArticleDOI
Nonsense-mediated mRNA decay: a 'nonsense' pathway makes sense in stem cell biology.
TL;DR: The recent findings on biological roles of NMD factors in embryonic and tissue-specific stem cells are summarized and the possible mechanisms of N MD in regulating stem cell fates are discussed.
Journal ArticleDOI
Defining the Contribution of MC1R Physiological Ligands to ATR Phosphorylation at Ser435, a Predictor of DNA Repair in Melanocytes
TL;DR: It is reported that melanocyte stimulating hormone (α-MSH) or adrenocorticotropic hormone (ACTH) induce ATR-pS435, enhance XPA’s association with UV-damaged DNA and optimize melanocytic NER, and the data suggest that ATS435 may be a useful biomarker for the DNA repair-deficient MC1R phenotype.
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.