Activation of p53 transcriptional activity requires ATM's kinase domain and multiple N-terminal serine residues of p53

Turenne, Gaetan A.; Paul, Proma; Laflair, Lareina; Price, Brendan D.

doi:10.1038/sj.onc.1204665

Cited by 95 publications

(60 citation statements)

References 61 publications

(131 reference statements)

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“…HeLa Tip60mt cells had decreased basal kinase activity that was not activated by exposure to bleomycin. ATM's kinase activity is required for ATM to regulate cell survival after exposure to IR (17). The failure to fully activate ATM in HeLa Tip60mt cells implies that these cells should be more sensitive to IR.…”

Section: Resultsmentioning

confidence: 99%

A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM

Sun

Jiang

Chen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

644

658

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FATC domain ͉ TRRAP ͉ NuA4 ͉ chromatin remodeling T he product of the ataxia telangiectasia (AT) gene, the AT mutant (ATM) protein kinase, is a key component of the signal-transduction pathway activated by DNA damage (1). In response to DNA strand breaks, ATM's kinase activity is upregulated, and ATM becomes autophosphorylated on Ser 1981 (2). ATM autophosphorylation initiates the conversion of the inactive ATM dimer to an active, monomeric ATM. ATM then phosphorylates multiple proteins involved in the DNA damage response, including nbs1, p53, chk2, and SMC1 (1, 3). These phosphorylated proteins, in turn, regulate the two key responses to DNA damage: the activation of cell-cycle checkpoints and the initiation of DNA repair.Although the downstream signaling pathways activated by ATM are well characterized, the mechanism by which DNA strand breaks are detected and how this leads to activation of ATM's kinase activity are less clear. The Mre11͞Rad50͞Nbs1 (MRN) complex, a DNA-binding complex involved in the detection and repair of DNA damage, may play a role in regulating ATM activity. MRN functions as an adaptor protein that links activated ATM with its target proteins [including chk2 (4) and SMC1 (3)] to allow productive phosphorylation (5, 6). Biochemical studies have shown that the DNA-dependent activation of ATM's kinase activity requires the functional MRN complex (7,8). However, although several studies have demonstrated that activation of ATM's kinase activity in cells lacking functional MRN complex is reduced (6, 9), other studies have shown that ATM activation is relatively normal in MRN-defective cells (5, 10). Furthermore, other proteins, including the p18 tumorsuppressor protein (11), have been shown to participate in ATM activation. Thus, although the MRN complex may regulate ATM activation under certain conditions, additional protein factors may also be required for ATM activation in vivo.Recent studies have shown that the repair of DNA doublestrand breaks requires the remodeling of chromatin structure (12-14). Furthermore, ATM can be activated by changes in chromatin structure that occur independently of DNA damage (2), leading to the proposal that ATM activation is mediated by alterations in chromatin structure at sites of DNA damage rather than through direct activation of ATM by strand breaks (1, 2). Chromatin remodeling is linked to the posttranslational modification of histones through phosphorylation, methylation, and acetylation (15). Histone acetyltransferases (HATs) can acetylate both histones and several nonhistone proteins (13,15). Here, we examined whether Tip60, a HAT previously implicated in the DNA-damage response, provides the link between DNA strand breaks in chromatin and the activation of ATM. The results indicate that DNA damage induces rapid acetylation of ATM by a mechanism that depends on the Tip60 HAT. Suppression of Tip60 blocks activation of ATM's kinase activity and sensitizes cells to ionizing radiation (IR). Furthermore, the FATC domain of ATM mediates the interaction bet...

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Section: Resultsmentioning

confidence: 99%

A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM

Sun

Jiang

Chen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

644

658

View full text Add to dashboard Cite

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“…2a). The ability of ATM to phosphorylate and activate key target proteins is required for ATM to regulate the cell response to ionizing radiation (21). Because the FATC domain of ATM is adjacent to the kinase domain, the FATC domain may influence the ability of ATM to phosphorylate key target proteins.…”

Section: Resultsmentioning

confidence: 99%

The FATC Domains of PIKK Proteins Are Functionally Equivalent and Participate in the Tip60-dependent Activation of DNA-PKcs and ATM

Jiang¹,

Sun²,

Chen

et al. 2006

Journal of Biological Chemistry

120

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“…This is in line with current concepts proposing posttranslational modification of p53 at either the N-or Cterminus to affect stability regulation in general, with serine 15-phosphorylation being a prerequisite for the transcriptional activity of p53 in particular (Dumaz and Meek, 1999). Studies with p53 N-terminal mutations at serines 15, 20, 33 or 37 indicated multiple and functionally overlapping phosphorylation sites to control p53 activity in response to DNA damage (Shieh et al, 1997;Dumaz and Meek, 1999;Hirao et al, 2000;Turenne et al, 2001). Whether kinases such as ATR or DNA-PK, known to be involved in post-translational modification of p53, are engaged in transmitting the NO signal needs further investigations.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide induces phosphorylation of p53 and impairs nuclear export

et al. 2003

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The tumor suppressor p53 accumulates under diverse stress conditions and affects cell cycle progression and/or apoptosis. This has been exemplified for endogenously produced or exogenously supplied nitric oxide (NO) and thus accounts at least in part for pathophysiological signaling of that bioactive molecule, although detailed mechanisms remain to be elucidated. By using luciferase reporter assays, we show that NO stabilized a transcriptionally active p53 protein. Considering that p53 is targeted by murine double minute (Mdm2) for ubiquitination and subsequent proteasomal degradation and knowing that this interaction is impaired by, for example, UV-treatment with concomitant stabilization of p53 we questioned the p53/Mdm2 interaction in the presence of NO. Although p53 became phosphorylated at serine 15 under the impact of NO, coimmunoprecipitation with Mdm2 and ubiquitination remained intact, thus excluding any interference of NO with this pathway. The importance of N-terminal p53 phosphorylation was verified with p53 mutants where the first six serine residues have been converted to alanine, and which do not accumulate in response to NO. Regulation of p53 stability can be also achieved by affecting nuclear-cytoplasmic shuttling and it was presented that leptomycin B, an inhibitor of nuclear export, caused p53 accumulation. Cell fractionation and immunofluorescence staining following NO-treatment revealed predominant nuclear accumulation of p53 in close association with serine 15-phosphorylation, which suggests impaired nuclear-cytoplasmic shuttling. This was verified by heterokaryon analysis. We conclude that attenuated nuclear export contributes to stabilization and activation of p53 under the influence of NO.

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Activation of p53 transcriptional activity requires ATM's kinase domain and multiple N-terminal serine residues of p53

Cited by 95 publications

References 61 publications

A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM

A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM

The FATC Domains of PIKK Proteins Are Functionally Equivalent and Participate in the Tip60-dependent Activation of DNA-PKcs and ATM

Nitric oxide induces phosphorylation of p53 and impairs nuclear export

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