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
Citations
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ATM kinase inhibition preferentially sensitizes p53 mutant glioma to ionizing radiation.
Laura Biddlestone-Thorpe,Muhammad Sajjad,Elizabeth Rosenberg,Jason M. Beckta,Nicholas C.K. Valerie,Mary E. Tokarz,Bret R. Adams,Alison F. Wagner,Ashraf Khalil,Donna Gilfor,Sarah E. Golding,Sumitra Deb,David G. Temesi,Alan Lau,Mark J. O'Connor,Kevin S. Choe,Luis F. Parada,Sang Kyun Lim,Nitai D. Mukhopadhyay,Kristoffer Valerie +19 more
TL;DR: The results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.
Journal ArticleDOI
Repairing breaks in the plant genome: the importance of keeping it together
TL;DR: This review will survey recent advances in understanding of plant responses to chromosomal breaks, including the sources of DNA damage, the detection and signalling of DSBs, mechanisms of D SB repair, the role of chromatin structure in repair, DNA damage signalling and the link between plant recombination pathways and transgene integration.
Journal ArticleDOI
Regulation of DNA-End Resection by hnRNPU-like Proteins Promotes DNA Double-Strand Break Signaling and Repair
Sophie E. Polo,Andrew N. Blackford,J. Ross Chapman,Linda Baskcomb,Serge Gravel,Andre Rusch,Anoushka Thomas,Rachel Blundred,Philippa Smith,Julia Kzhyshkowska,Julia Kzhyshkowska,Thomas Dobner,A. Malcolm R. Taylor,Andrew S. Turnell,Grant S. Stewart,Roger J.A. Grand,Stephen P. Jackson +16 more
TL;DR: It is established that heterogeneous nuclear ribonucleoprotein U-like proteins 1 and 2 function downstream of MRN and CtBP-interacting protein (CtIP) to promote recruitment of the BLM helicase to DNA breaks and provide insights into how mammalian cells respond to DSBs.
Journal ArticleDOI
Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination
Sharanya Sivanand,Seth D. Rhoades,Qinqin Jiang,Joyce V. Lee,Joseph L. Benci,Jingwen Zhang,Salina Yuan,Isabella Viney,Steven Zhao,Alessandro Carrer,Michael J. Bennett,Andy J. Minn,Aalim M. Weljie,Roger A. Greenberg,Kathryn E. Wellen +14 more
TL;DR: The spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice, and nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ataxia telangiectasia mutated (ATM) and AKT following DNA damage.
Journal ArticleDOI
N6-methyladenosine modification in mRNA: machinery, function and implications for health and diseases.
Arpita Maity,Biswadip Das +1 more
TL;DR: Reversible mRNA methylation adds another layer of regulation at the post‐transcriptional level in the gene expression programme of eukaryotes that finely sculpts a highly dynamic proteome in order to respond to diverse cues during cellular differentiation, immune tolerance, and neuronal signalling.
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.