ATP Activates Ataxia-Telangiectasia Mutated (ATM) in Vitro

Kozlov, Sergei; Gueven, Nuri; Keating, Katherine E.; Ramsay, Jonathan; Lavin, Martin F.

doi:10.1074/jbc.m300003200

Cited by 90 publications

(66 citation statements)

References 57 publications

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“…This lack of requirement for autophosphorylation for activation in vitro was similar to that reported earlier by Bakkenist and Kastan (2003). Indeed, there are several reports of ATM activation in vitro and in vivo without the requirement for S1981 autophosphorylation (Kozlov et al, 2003;Hamer et al, 2004;Powers et al, 2004).…”

Section: Viral Infection and In Vitro Models To Investigate The Role supporting

confidence: 87%

“…Evidence using rare genetic disorders and mouse models While the recruitment of the MRN complex to damaged DNA is rapid, so too is the activation of ATM (Bakkenist and Kastan, 2003;Kozlov et al, 2003), making it difficult to discern the sequence of events involved. If the MRN complex were the sensor of DNA breaks then it might be expected that it would be upstream of ATM activation.…”

Section: Atm Is Recruited To and Activated By The Mrn Complexmentioning

confidence: 99%

“…This might create a situation where an increased pool size of Atm in the vicinity of the break led to Atm activation without the need for autophosphorylation. Activation can occur in vitro by adding ATP or DNA ends to ATM without a requirement for pS1981 (Kozlov et al, 2003;Lee and Paull, 2005). Indeed, there are other examples of ATM activation without evidence of phosphorylation on S1981 (Hamer et al, 2004;Powers et al, 2004).…”

Section: Perspectivementioning

confidence: 99%

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ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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The recognition and repair of DNA double-strand breaks (DSBs) is a complex process that draws upon a multitude of proteins. This is not surprising since this is a lethal lesion if left unrepaired and also contributes to genome instability and the consequential risk of cancer and other pathologies. Some of the key proteins that recognize these breaks in DNA are mutated in distinct genetic disorders that predispose to agent sensitivity, genome instability, cancer predisposition and/or neurodegeneration. These include members of the Mre11 complex (Mre11/Rad50/ Nbs1) and ataxia-telangiectasia (A-T) mutated (ATM), mutated in the human genetic disorder A-T. The mre11 (MRN) complex appears to be the major sensor of the breaks and subsequently recruits ATM where it is activated to phosphorylate in turn members of that complex and a variety of other proteins involved in cellcycle control and DNA repair. The MRN complex is also upstream of ATM and ATR (A-T-mutated and rad3-related) protein in responding to agents that block DNA replication. To date, more than 30 ATM-dependent substrates have been identified in multiple pathways that maintain genome stability and reduce the risk of disease. We focus here on the relationship between ATM and the MRN complex in recognizing and responding to DNA DSBs.

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Section: Viral Infection and In Vitro Models To Investigate The Role supporting

confidence: 87%

Section: Atm Is Recruited To and Activated By The Mrn Complexmentioning

confidence: 99%

Section: Perspectivementioning

confidence: 99%

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ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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“…As already mentioned, Bakkenist and Kastan (2003) showed that autophosphorylation of ATM after DNA damage is required for monomerization. Immunoprecipitated ATM was also shown to be autophosphorylated in vitro during incubation with g 32 -ATP, and the preincubation with ATP correlated with higher levels of kinase activity in vitro (Kozlov et al, 2003). Later, other phosphorylation sites on ATM were found in addition to Ser1981, including Ser367 and Ser1893 (Kozlov et al, 2006).…”

Section: Atm Autophosphorylationmentioning

confidence: 91%

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

2007

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The ataxia-telangiectasia-mutated (ATM) protein kinase is rapidly and specifically activated in response to DNA double-strand breaks in eukaryotic cells. In this review, we summarize recent insights into the mechanism of ATM activation, focusing on the role of the Mre11/Rad50/Nbs1 (MRN) complex in this process. We also compare observations of the ATM activation process in different biological systems and highlight potential candidates for cellular factors that may participate in regulating ATM activity in human cells.

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“…What is clear is that divalent cations such as Mn 2 þ stimulate the in vitro kinase activity of ATM, perhaps by mimicking the effect of DNA on ATM (Durocher and Jackson, 2001;Jackson, 2001). Recently, two studies showed that ATM autophosphorylation is important for the activation of the associated kinase (Bakkenist and Kastan, 2003;Kozlov et al, 2003). It was proposed that ATM is sequestered in unperturbed cells as a dimer with its kinase domain interacting with an internal domain of a neighboring ATM molecule spanning S1981 (Bakkenist and Kastan, 2003).…”

Section: Atm Targets Involved In Dsb Repairmentioning

confidence: 99%

Regulation and mechanisms of mammalian double-strand break repair

2003

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The double-strand break (DSB) is believed to be one of the most severe types of DNA damage, and if left unrepaired is lethal to the cell. Several different types of repair act on the DSB. The most important in mammalian cells are nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR). NHEJ is the predominant type of DSB repair in mammalian cells, as opposed to lower eucaryotes, but HRR has recently been implicated in critical cell signaling and regulatory functions that are essential for cell viability. Whereas NHEJ repair appears constitutive, HRR is regulated by the cell cycle and inducible signal transduction pathways. More is known about the molecular details of NHEJ than HRR in mammalian cells. This review focuses on the mechanisms and regulation of DSB repair in mammalian cells, the signaling pathways that regulate these processes and the potential crosstalk between NHEJ and HRR, and between repair and other stress-induced pathways with emphasis on the regulatory circuitry associated with the ataxia telangiectasia mutated (ATM) protein.

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ATP Activates Ataxia-Telangiectasia Mutated (ATM) in Vitro

Cited by 90 publications

References 57 publications

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

Regulation and mechanisms of mammalian double-strand break repair

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