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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FOXOs: signalling integrators for homeostasis maintenance
TL;DR: Multiple upstream pathways regulate FOXO activity through post-translational modifications and nuclear–cytoplasmic shuttling of both FOXO and its regulators, suggesting that they function as homeostasis regulators to maintain tissueHomeostasis over time and coordinate a response to environmental changes.
Journal ArticleDOI
Deep sequencing reveals 50 novel genes for recessive cognitive disorders
Hossein Najmabadi,Hao Hu,Masoud Garshasbi,Tomasz Zemojtel,Seyedeh Sedigheh Abedini,Wei Chen,Masoumeh Hosseini,Farkhondeh Behjati,Stefan A. Haas,Payman Jamali,Agnes Zecha,Marzieh Mohseni,Lucia Püttmann,Leyla Nouri Vahid,C Jensen,Lia Abbasi Moheb,M Bienek,Farzaneh Larti,Ines Mueller,Robert Weissmann,Hossein Darvish,Klaus Wrogemann,Klaus Wrogemann,Valeh Hadavi,Bettina Lipkowitz,Sahar Esmaeeli-Nieh,Dagmar Wieczorek,Roxana Kariminejad,Saghar Ghasemi Firouzabadi,Monika Cohen,Zohreh Fattahi,Imma Rost,Faezeh Mojahedi,Christoph Hertzberg,Atefeh Dehghan,Anna Rajab,Mohammad Javad Soltani Banavandi,Julia Hoffer,Masoumeh Falah,Luciana Musante,Vera M. Kalscheuer,Reinhard Ullmann,Andreas W. Kuss,Andreas Tzschach,Kimia Kahrizi,Hans-Hilger Ropers +45 more
TL;DR: This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes.
Journal ArticleDOI
Broadening horizons: the role of ferroptosis in cancer.
TL;DR: In this paper, the key molecular mechanisms of ferroptosis, including crosstalk with tumour-associated signalling pathways, and discuss potential therapeutic applications of the process are presented.
Journal ArticleDOI
BAP1 loss defines a new class of renal cell carcinoma
Samuel Peña-Llopis,Silvia Vega-Rubin-de-Celis,Silvia Vega-Rubin-de-Celis,Arnold Liao,Nan Leng,Andrea Pavia-Jimenez,Andrea Pavia-Jimenez,Shanshan Wang,Shanshan Wang,Toshinari Yamasaki,Toshinari Yamasaki,Leah Zhrebker,Leah Zhrebker,Sharanya Sivanand,Sharanya Sivanand,Patrick Spence,Patrick Spence,Lisa N. Kinch,Tina Hambuch,Suneer Jain,Yair Lotan,Vitaly Margulis,Arthur I. Sagalowsky,Pia Banerji Summerour,Wareef Kabbani,S. W Wendy Wong,Nick V. Grishin,Marc Laurent,Xian Jin Xie,Christian D. Haudenschild,Mark T. Ross,David R. Bentley,Payal Kapur,James Brugarolas +33 more
TL;DR: The results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
Journal ArticleDOI
The RIDDLE Syndrome Protein Mediates a Ubiquitin-Dependent Signaling Cascade at Sites of DNA Damage
Grant S. Stewart,Stephanie Panier,Stephanie Panier,Kelly Townsend,Abdallah Al-Hakim,Nadine K. Kolas,Edward S. Miller,Shinichiro Nakada,Jarkko Ylanko,Jarkko Ylanko,Signe Olivarius,Megan Mendez,Ceri E. Oldreive,Jan Wildenhain,Andrea Tagliaferro,Laurence Pelletier,Laurence Pelletier,Nadine Taubenheim,Anne Durandy,Philip J. Byrd,Tatjana Stankovic,A. Malcolm R. Taylor,Daniel Durocher,Daniel Durocher +23 more
TL;DR: It is reported that the ubiquitin ligase RNF168 is mutated in the RIDDLE syndrome, a recently discovered immunodeficiency and radiosensitivity disorder and their loss is the likely cause of the cellular and developmental phenotypes associated with RIDdLE syndrome.
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.