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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Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes
Xu Li,Wenqi Wang,Jiadong Wang,Anna Malovannaya,Yuanxin Xi,Wei Li,Rudy Guerra,David H. Hawke,Jun Qin,Junjie Chen +9 more
TL;DR: This study performs proteomics analyses of soluble and chromatin‐associated complexes of 56 transcription factors, including the targets of many signalling pathways involved in development and cancer, and 37 members of the Forkhead box (FOX) TF family, and found that most TFs form very distinct protein complexes on and off chromatin.
Journal ArticleDOI
ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
Gabriel Balmus,Domenic Pilger,Julia Coates,Mukerrem Demir,Matylda Sczaniecka-Clift,Ana C. Barros,Michael Woods,Beiyuan Fu,Fengtang Yang,Elisabeth Chen,Matthias Ostermaier,Tatjana Stankovic,Hannes Ponstingl,Mareike Herzog,Mareike Herzog,Kosuke Yusa,Francisco Munoz Martinez,Stephen T. Durant,Yaron Galanty,Petra Beli,David J. Adams,Allan Bradley,Emmanouil Metzakopian,Emmanouil Metzakopian,Josep V. Forment,Josep V. Forment,Stephen P. Jackson +26 more
TL;DR: It is established that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions.
Journal ArticleDOI
The NBS1–Treacle complex controls ribosomal RNA transcription in response to DNA damage
Dorthe Helena Larsen,Flurina J. Hari,Julie A. Clapperton,Myriam Gwerder,Katrin Gutsche,Matthias Altmeyer,Stephanie Jungmichel,Luis I. Toledo,Daniel Fink,Maj-Britt Rask,Merete Grøfte,Claudia Lukas,Michael L. Nielsen,Stephen J. Smerdon,Jiri Lukas,Manuel Stucki +15 more
TL;DR: An in trans signalling mechanism that triggers pan-nuclear silencing of rRNA transcription in response to DNA damage is discovered that is associated with transient recruitment of the Nijmegen breakage syndrome protein 1 (NBS1), a central regulator of DNA damage responses, into the nucleoli.
Journal ArticleDOI
The importance of safeguarding genome integrity in germination and seed longevity
TL;DR: Recent studies identified that maintenance of genome integrity is particularly important to the seed stage of the plant lifecycle, revealing new insight into the physiological roles of plant DNA repair and recombination mechanisms.
Journal ArticleDOI
The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer.
Johanna Tommiska,J Bartkova,Mira Heinonen,Laura Hautala,Outi Kilpivaara,Hannaleena Eerola,Kristiina Aittomäki,Barbara Hofstetter,Jiri Lukas,K. von Smitten,Carl Blomqvist,Ari Ristimäki,Päivi Heikkilä,J Bartek,Heli Nevanlinna +14 more
TL;DR: A model of ‘conditional haploinsufficiency’ for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM is proposed, with implications for genomic instability and curability of diverse subsets of human breast cancer.
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.