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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Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway
Hyungjin Kim,Alan D. D'Andrea +1 more
TL;DR: Recent advances in understanding of the downstream ICL repair steps initiated by ubiquitin-mediated FA pathway activation are reviewed.
Journal ArticleDOI
The Aging Stress Response
TL;DR: The systems biology of stress response signaling thus provides a new approach to the understanding and potential treatment of age-related diseases.
Journal ArticleDOI
System-wide changes to SUMO modifications in response to heat shock
Filip Golebiowski,Ivan Matic,Michael H. Tatham,Christian Cole,Yili Yin,Akihiro Nakamura,Juergen Cox,Geoffrey J. Barton,Matthias Mann,Ronald T. Hay +9 more
TL;DR: This comprehensive proteomic analysis of the substrates of a ubiquitin-like modifier (Ubl) identifies a pervasive role for SUMO proteins in the biologic response to hyperthermic stress.
Journal ArticleDOI
Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair
Jennifer Svendsen,Agata Smogorzewska,Agata Smogorzewska,Mathew E. Sowa,Brenda C. O'Connell,Steven P. Gygi,Stephen J. Elledge,Stephen J. Elledge,J. Wade Harper +8 more
TL;DR: SLX4 assembles a modular toolkit for repair of specific types of DNA lesions and is critical for cellular responses to replication fork failure, and is identified as the human ortholog of the budding yeast DNA repair factor Slx4p and D. melanogaster MUS312.
Journal ArticleDOI
Linear Motif Atlas for Phosphorylation-Dependent Signaling
Martin L. Miller,Martin L. Miller,Lars Juhl Jensen,Francesca Diella,Claus Jørgensen,Michele Tinti,Lei Li,Marilyn Hsiung,Sirlester A. Parker,Jennifer Bordeaux,Thomas Sicheritz-Pontén,Marina Olhovsky,Adrian Pasculescu,Jes Alexander,Stefan Knapp,Nikolaj Blom,Peer Bork,Peer Bork,Shawn S.-C. Li,Gianni Cesareni,Tony Pawson,Benjamin E. Turk,Michael B. Yaffe,Søren Brunak,Søren Brunak,Rune Linding,Rune Linding,Rune Linding +27 more
TL;DR: The resulting atlas of linear motifs revealed that oncogenic kinases tends to be less specific in the target sequences they phosphorylate than their non-oncogenic counterparts, that autophosphorylation sites tend to be more variable than other substrates of a given kinase, and that coupling interaction domains with kinase domains may allow phosphorylation site specificity to be low while still maintaining substrate specificity.
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.