A role for ATR in the DNA damage-induced phosphorylation of p53
Randal S. Tibbetts,Kathryn M. Brumbaugh,Josie M. Williams,Jann N. Sarkaria,William A. Cliby,Sheau-Yann Shieh,Yoichi Taya,Carol Prives,Robert T. Abraham +8 more
TLDR
Evidence that the ATM-Rad3-related protein ATR regulates phosphorylation of Ser-15 in DNA-damaged cells is provided and it is suggested that p53 is a target for phosphorylated by ATR by blocking UV-induced Ser- 15 phosphorylations in a time-independent manner.Abstract:
Phosphorylation at Ser-15 may be a critical event in the up-regulation and functional activation of p53 during cellular stress. In this report we provide evidence that the ATM–Rad3-related protein ATR regulates phosphorylation of Ser-15 in DNA-damaged cells. Overexpression of catalytically inactive ATR (ATRki) in human fibroblasts inhibited Ser-15 phosphorylation in response to γ-irradiation and UV light. In γ-irradiated cells, ATRki expression selectively interfered with late-phase Ser-15 phosphorylation, whereas ATRki blocked UV-induced Ser-15 phosphorylation in a time-independent manner. ATR phosphorylated p53 at Ser-15 and Ser-37 in vitro, suggesting that p53 is a target for phosphorylation by ATR in DNA-damaged cells.read more
Citations
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The DNA damage response: putting checkpoints in perspective
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ATM and related protein kinases: safeguarding genome integrity
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DNA double-strand breaks: signaling, repair and the cancer connection.
TL;DR: Recent progress is described in understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation—the DNA double-strand break (DSB).
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Cell cycle checkpoint signaling through the ATM and ATR kinases
TL;DR: These checkpoints contain, as their most proximal signaling elements, sensor proteins that scan chromatin for partially replicated DNA, DNA strand breaks, or other abnormalities, and translate these DNA-derived stimuli into biochemical signals that modulate the functions of specific downstream target proteins.
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An oncogene-induced DNA damage model for cancer development.
TL;DR: Oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.
References
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Mdm2 promotes the rapid degradation of p53
TL;DR: It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
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Regulation of p53 stability by Mdm2
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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.
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DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2
TL;DR: Using purified DNA-dependent protein kinase (DNA-PK), it is demonstrated that phosphorylation of p53 at serine 15 and 37 impairs the ability of MDM2 to inhibit p53-dependent transactivation and provides a plausible mechanism by which the induction of p 53 can be modulated by DNA-PK in response to DNA damage.
Journal ArticleDOI
Cell Cycle Checkpoints: Preventing an Identity Crisis
TL;DR: Signal transduction pathways that transmit checkpoint signals in response to DNA damage, replication blocks, and spindle damage are revealed, underscoring the conservation of cell cycle regulatory machinery.