KAP1, a Novel Substrate for PIKK Family Members, Colocalizes with Numerous Damage Response Factors at DNA Lesions

White, David E.; Negorev, Dmitri; Peng, Hongzhuang; Ivanov, Alexey V.; Maul, Gerd G.; Rauscher, Frank J.

doi:10.1158/0008-5472.can-06-4138

Cited by 124 publications

(132 citation statements)

References 19 publications

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“…Re-expression of Flag-tagged ATM WT but not Y370F mutant rescued p-CHK2 IRIF ( Figure 4E), indicating that ATM Y370 phosphorylation is also involved in p-CHK2 IRIF formation. Similar results were observed that only restoring expression of Flag-tagged ATM WT but not the Y370F mutant rescued ATM-mediated p-KAP1 [49,50] IRIF in ATM-depleted HeLa cells (Supplementary information, Figure S4G). We further investigated whether ATM Y370 phosphorylation is also involved in S343 phosphorylation of NBS1, as ATM serves as an upstream kinase in the ATM-NBS1-SMC1 signaling for cell cycle checkpoint [51,52].…”

Section: Egfr Regulates Ddr Via Atm Y370 Phosphorylationsupporting

confidence: 82%

Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

et al. 2015

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Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest 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.

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Section: Egfr Regulates Ddr Via Atm Y370 Phosphorylationsupporting

confidence: 82%

Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

et al. 2015

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“…This regulation by DNA-PK but not by ATM is striking because many of the proteins targeted during DNA repair, such as H2AX, 53BP1, and KAP1, can be phosphorylated by either ATM or DNA-PK (13,15,34). Although DNA-PK inhibition diminishes PA200 on chromatin by 34-40%, there may also be other regulators (such as ATR) of PA200 responsiveness to IR-induced damage.…”

Section: Discussionmentioning

confidence: 97%

Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability

Blickwedehl

Agarwal

Seong

et al. 2008

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

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Proteasome activator PA200 enhances proteasome-mediated cleavage after acidic residues in vitro; however, its role within cells is not known. Here, we show that, in response to ionizing radiation, PA200 forms hybrid proteasomes with 19S caps and 20S core proteasomes that accumulate on chromatin, leading to an increase in proteolytic activity. Unlike many other proteins that respond to DNA damage, the response of PA200 appears to be independent of Ataxia Telangiectasia Mutated and p53, but dependent on DNAdependent protein kinase activity. Nonetheless, PA200 is critical because PA200-knockdown cells show genomic instability and reduced survival after exposure to ionizing radiation. This phenotype is reproduced by specific inhibition of postglutamyl activity of proteasomes, but combined treatment with PA200 siRNA and postglutamyl inhibitor does not show additive effects on survival. Together, these data suggest a unique role for PA200 in genomic stability that is likely mediated through its ability to enhance postglutamyl cleavage by proteasomes.ATM ͉ chromatin ͉ DNA-dependent protein kinase ͉ ionizing radiation ͉ DNA damage

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“…17,18 Phosphorylated KAP1 spreads rapidly throughout chromatin and has been implicated in an ATM kinase-dependent chromatin decondensation within five minutes of exposure to agents that introduce DNA DSBs. Disruption of KAP1 renders cells hypersensitive to agents that introduce DNA DSBs.…”

Section: Introductionmentioning

confidence: 99%

Irreversible chromosome damage accumulates rapidly in the absence of ATM kinase activity

White¹,

Choi²,

Bakkenist³

2008

Cell Cycle

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Mutations in the ATM kinase cause the neurodegenerative disorder ataxia telangiectasia (A-T) and affected individuals are exquisitely radiation-sensitive and cancer-prone. Cells derived from A-T individuals contain chromosome aberrations and exhibit profound cellular radiosensitivity. ATM is an apical kinase critical for the activation of cell cycle checkpoints and the induction of apoptosis in irradiated cells. However, defects in these pathways are insufficient to account for the chromosomal instability seen in A-T cells. We show here that the small molecule KU55933 can be used as a "molecular switch" to selectively and transiently inhibit ATM kinase activity in cells. We subsequently show that the cellular radiosensitization seen when ATM kinase activity is inhibited for one hour following exposure to g-rays, accounts for over 70% of the total cellular radiosensitization seen when ATM kinase activity is inhibited for 17 h. Finally, we show that inhibition of ATM kinase activity for one hour following exposure to irradiation doubles the number of chromosome aberrations occurring in late-S-and G 2 -, but not M-phase, cells. These observations are unexpected and suggest that irreversible chromosome damage accumulates very rapidly when ATM kinase activity is transiently inhibited following irradiation. We propose that we have revealed an essential, yet previously undescribed, role for ATM kinase in suppressing chromosomal instability.

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KAP1, a Novel Substrate for PIKK Family Members, Colocalizes with Numerous Damage Response Factors at DNA Lesions

Cited by 124 publications

References 19 publications

Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability

Irreversible chromosome damage accumulates rapidly in the absence of ATM kinase activity

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