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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Germline BAP1 mutations predispose also to multiple basal cell carcinomas.
A. de la Fouchardière,Odile Cabaret,L. Savin,Patrick Combemale,H. Schvartz,Clotilde Penet,Valérie Bonadona,Nadem Soufir,Brigitte Bressac-de Paillerets +8 more
TL;DR: Cutaneous follow‐up of BAP1 carriers should not only aim to detect melanocytic neoplasms but also BCCs, perhaps in relation with chronic sun exposure and melanocortin 1 receptor (MC1R) variants.
Journal ArticleDOI
UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors
Ron D. Jachimowicz,Filippo Beleggia,Jörg Isensee,Bhagya Bhavana Velpula,Jonas Goergens,Matias A. Bustos,Markus A. Doll,Anjana Shenoy,Cintia Checa-Rodríguez,Janica L Wiederstein,Keren Baranes-Bachar,Christoph Bartenhagen,F Hertwig,Nizan Teper,Tomohiko Nishi,Anna Schmitt,Felix Distelmaier,Hermann-Josef Lüdecke,Beate Albrecht,Marcus Krüger,Björn Schumacher,Tamar Geiger,Dave S.B. Hoon,Pablo Huertas,Matthias Fischer,Tim Hucho,Martin Peifer,Yael Ziv,H. Christian Reinhardt,Dagmar Wieczorek,Yosef Shiloh +30 more
TL;DR: UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLn4-overexpressing tumors.
Journal ArticleDOI
PBRM1 and BAP1 as novel targets for renal cell carcinoma
TL;DR: The evidence that implicated PBRM1 and BAP1 as renal cancer driver genes is reviewed, an update on the function of the gene products is provided, and speculation on how mutations in these genes may be exploited therapeutically is speculated on.
Journal ArticleDOI
ATR kinase is required for global genomic nucleotide excision repair exclusively during S phase in human cells
TL;DR: A novel flow cytometry-based DNA repair assay is developed that allows precise evaluation of GG-NER kinetics as a function of cell cycle and reveals a highly novel role for ATR in the regulation ofGG-NER uniquely during S phase of the cell cycle, and indicates that many human cancers may be characterized by a defect in this regulation.
Journal ArticleDOI
MicroRNAs, the DNA damage response and cancer
TL;DR: The role of DNA damage response microRNAs in cancer etiology and sensitivity to ionizing radiation and other DNA damaging therapeutic agents is discussed.
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.