ATM: From Gene to Function
Galit Rotman,Yosef Shiloh +1 more
TLDR
It is shown that ATM is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents or by normal processes, such as meiotic or V(D)J recombination, which involve the activation of cell cycle checkpoints, DNA repair and apoptosis.Abstract:
The identification of ATM , the gene responsible for the pleiotropic recessive disease ataxia telangiectasia, has initiated extensive research to determine the functions of its multifaceted protein product. The ATM protein belongs to a family of protein kinases that share similarities at their C-terminal region with the catalytic domain of phosphatidylinositol 3-kinases. Studies with ataxia telangiectasia (A-T) cells and Atm-deficient mice have shown that ATM is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents or by normal processes, such as meiotic or V(D)J recombination. These responses involve the activation of cell cycle checkpoints, DNA repair and apoptosis. Other roles outside the cell nucleus might be carried out by the cytoplasmic fraction of ATM. In addition, ATM appears to function as a 'caretaker', suppressing tumorigenesis in specific T cell lineages.read more
Citations
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Genetic instabilities in human cancers
TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
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Genome maintenance mechanisms for preventing cancer
TL;DR: This review summarizes the main DNA caretaking systems and their impact on genome stability and carcinogenesis.
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Chromosomal stability and the DNA double-stranded break connection.
TL;DR: Interactions between both double-stranded break-repair pathways and other cellular processes, such as cell-cycle regulation and replication, are being unveiled.
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Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM.
Ian Hickson,Yan Zhao,Caroline Richardson,Sharon J. Green,Niall M. B. Martin,Alisdair I. Orr,Philip Michael Reaper,Stephen P. Jackson,Nicola J. Curtin,Graeme C. M. Smith +9 more
TL;DR: KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase, which did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage.
Journal Article
Inhibition of ATM and ATR Kinase Activities by the Radiosensitizing Agent, Caffeine
Jann N. Sarkaria,Ericka C. Busby,Randal S. Tibbetts,Pia Roos,Yoichi Taya,Larry M. Karnitz,Robert T. Abraham +6 more
TL;DR: Caffeine inhibits the catalytic activity of both ATM and the related kinase, ATM and Rad3-related (ATR), at drug concentrations similar to those that induce radiosensitization, suggesting that both proteins are relevant targets for the development of novel anticancer agents.
References
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p53 is required for radiation-induced apoptosis in mouse thymocytes
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Journal ArticleDOI
A single ataxia telangiectasia gene with a product similar to pi-3 kinase
Kinneret Savitsky,Anat Bar-Shira,Shlomit Gilad,Galit Rotman,Yael Ziv,Lina Vanagaite,Danilo A. Tagle,Sara Smith,Tamar Uziel,Sharon Sfez,Maya Ashkenazi,Iris Pecker,Moshe Frydman,Reli Harnik,Sankhavaram R. Patanjali,Andrew D. Simmons,Gregory A. Clines,Adam Sartiel,Richard A. Gatti,Luciana Chessa,Ozden Sanal,Martin F. Lavin,Nicolaas G. J. Jaspers,A. Malcolm R. Taylor,Colin F. Arlett,Toru Miki,Sherman M. Weissman,Michael Lovett,Francis S. Collins,Yosef Shiloh +29 more
TL;DR: A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia was identified by positional cloning on chromosome 11q22-23 and encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control.
Journal ArticleDOI
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Journal ArticleDOI
DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2
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Journal Article
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TL;DR: The results support the idea that WAF1/CIP1 is a critical downstream effector in the p53-specific pathway of growth control in mammalian cells.
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