DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation

@article{Bakkenist2003DNADA,
  title={DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation},
  author={Christopher J. Bakkenist and Michael B. Kastan},
  journal={Nature},
  year={2003},
  volume={421},
  pages={499-506}
}
The ATM protein kinase, mutations of which are associated with the human disease ataxia–telangiectasia, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described ‘FAT’ domain. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer… Expand
Structure of the human dimeric ATM kinase
TLDR
The unanticipated domain organization of ATM provides a basis for understanding its mechanism of inhibition and the structure of dimeric ATM in its resting state is determined. Expand
Rapid activation of ATM on DNA flanking double-strand breaks
TLDR
It is demonstrated that linear DNA fragments added to Xenopus egg extracts mimic DSBs in genomic DNA and provide a platform for ATM autophosphorylation and activation, revealing a direct role for DNA flanking DSB ends in ATM activation. Expand
Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM.
TLDR
It is shown that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA- PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells, and negatively regulates ATM activity through phosphorylation of ATM. Expand
Mechanisms of ATM Activation.
  • T. Paull
  • Biology, Medicine
  • Annual review of biochemistry
  • 2015
TLDR
Functional similarities between the activation mechanisms of ATM, phosphatidylinositol 3-kinases (PI3Ks), and the other PI3K-like kinases are highlighted, as well as recent structural insights into their regulation. Expand
Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo
TLDR
It is shown that ATM-dependent responses at both cellular and organismal levels are functional in mice that express a triple serine mutant form of ATM as their sole ATM species, lending further support to the notion that ATM autophosphorylation correlates with the DNA damage–induced activation of the kinase but is not required for ATM function in vivo. Expand
Autophosphorylation and ATM Activation
TLDR
This work targeted the ATM phosphorylation sites, Ser367 and Ser2996, for further study by generating phosphospecific antibodies against these sites and demonstrated thatosphorylation of both was rapidly induced by radiation, providing further support for the importance of autophosphorylated in the activation and function of ATM in vivo. Expand
Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response
TLDR
A critical mechanism by which EGFR directly regulates ATM activation in DNA damage response is revealed, and it is suggested that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition. Expand
A new effector pathway links ATM kinase with the DNA damage response
TLDR
This work reports a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap, and indicates that the nuclear accumulation of Strap is a critical regulator in the damage response. Expand
Irreversible chromosome damage accumulates rapidly in the absence of ATM kinase activity
TLDR
It is proposed that an essential, yet previously undescribed, role for ATM kinase in suppressing chromosomal instability is revealed and it is suggested that irreversible chromosome damage accumulates very rapidly when ATM Kinase activity is transiently inhibited following irradiation. Expand
Detecting ATM-dependent chromatin modification in DNA damage response.
TLDR
This review summarizes the multiple approaches used to discern the role of ATM and other associated proteins in chromatin modification in response to DNA damage and shows that ATM activation is tightly regulated by chromatin modifications. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 59 REFERENCES
Enhanced phosphorylation of p53 by ATM in response to DNA damage.
TLDR
Various damage-induced responses may be activated by enhancement of the protein kinase activity of ATM, and this activity was markedly enhanced within minutes after treatment of cells with a radiomimetic drug. Expand
Purification and DNA binding properties of the ataxia-telangiectasia gene product ATM.
  • G. Smith, R. B. Cary, +4 authors S. Jackson
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1999
TLDR
The results provide a biochemical assay system for ATM, support genetic data indicating distinct roles for DNA-dependent protein kinase and ATM, and suggest how ATM may signal the presence of DNA damage to p53 and other downstream effectors. Expand
ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response
TLDR
It is reported that Nbs is specifically phosphorylated in response to γ-radiation, ultraviolet light and exposure to hydroxyurea, and phosphorylation of Nbs by Atm is critical for certain responses of human cells to DNA damage. Expand
Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.
The p53 tumor suppressor protein is activated and phosphorylated on serine-15 in response to various DNA damaging agents. The gene product mutated in ataxia telangiectasia, ATM, acts upstream of p53Expand
Caffeine Abolishes the Mammalian G2/M DNA Damage Checkpoint by Inhibiting Ataxia-Telangiectasia-mutated Kinase Activity*
TLDR
A model wherein caffeine abrogates the G2/M checkpoint by targeting the ATM-Chk2/Cds1 pathway is proposed; by inhibiting ATM, it prevents the serine 216 phosphorylation of Cdc25C in the nucleus. Expand
ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage.
The p53 tumor suppressor protein, a key regulator of cellular responses to genotoxic stress, is stabilized and activated after DNA damage. The rapid activation of p53 by ionizing radiation andExpand
Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members*
TLDR
A general phosphorylation consensus sequence for ATM is determined and putative in vitro targets are identified by using glutathioneS-transferase peptides as substrates by utilizing p53 peptide mutagenesis analysis. Expand
ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway
TLDR
Observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases. Expand
Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage.
TLDR
It is shown that the protein kinase, Atm, which belongs to a family of phosphatidylinositol 3-kinases that regulate cell cycle checkpoints and DNA recombination and repair, phosphorylates Smc1 protein after ionizing irradiation. Expand
Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.
TLDR
In vivo, results suggest that in vivo, Chk2 is directly phosphorylated by ATM in response to IR and that Chk 2 is regulated by phosphorylation of the SCD. Expand
...
1
2
3
4
5
...