DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation

  title={DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation},
  author={Christopher J. Bakkenist and Michael B. Kastan},
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… 

Structure of the human dimeric ATM kinase

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.

Rapid activation of ATM on DNA flanking double-strand breaks

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.

Mechanisms of ATM Activation.

  • T. Paull
  • Biology
    Annual review of biochemistry
  • 2015
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.

Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo

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.

Autophosphorylation and ATM Activation

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.

Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

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.

A new effector pathway links ATM kinase with the DNA damage response

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.

Detecting ATM-dependent chromatin modification in DNA damage response.

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.

Pharmacological inhibition of ATM by KU55933 stimulates ATM transcription

The degree of ATM activation during time-dependent treatment with genotoxic agents and the effects of ATM on phospho-induction and localization of its downstream substrates are investigated and a new cell-cycle-independent mechanism of ATM gene regulation following ATM kinase inhibition is demonstrated.



Enhanced phosphorylation of p53 by ATM in response to DNA damage.

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.

Purification and DNA binding properties of the ataxia-telangiectasia gene product ATM.

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.

ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response

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.

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 p53

Caffeine Abolishes the Mammalian G2/M DNA Damage Checkpoint by Inhibiting Ataxia-Telangiectasia-mutated Kinase Activity*

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.

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 and

ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway

Observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.

Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage.

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.

Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.

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.

DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139*

When mammalian cell cultures or mice are exposed to ionizing radiation in survivable or lethal amounts, novel mass components are found in the histone H2A region of two-dimensional gels. Collectively