Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM

Zhou, Yi; Lee, Ji-Hoon; Jiang, Wenxia; Crowe, Jennifer; Zha, Shan; Paull, Tanya T.

doi:10.1016/j.molcel.2016.11.004

Cited by 108 publications

(105 citation statements)

References 44 publications

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“…Therefore, indirect effect may not amplify p53 pulses. During the review, Zhou et al identified that DNA-PK phosphorylates ATM at multiple sites and inhibits ATM activity [23]. Our model inference is consistent with Zhou et al’s study.…”

Section: Discussionsupporting

confidence: 90%

Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

Sun

Shen

2017

Oncotarget

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During DNA double strand breaks (DSBs) repair, coordinated activation of phosphatidylinositol 3-kinase (PI3K)-like kinases can activate p53 signaling pathway. Recent findings have identified novel interplays among these kinases demonstrating amplified first p53 pulses under DNA-PK inhibition. However, no theoretical model has been developed to characterize such dynamics. In current work, we modeled the prolonged p53 pulses with DNA-PK inhibitor. We could identify a dose-dependent increase in the first pulse amplitude and width. Meanwhile, weakened DNA-PK mediated ATM inhibition was insufficient to reproduce such dynamic behavior. Moreover, the information flow was shifted predominantly to the first pulse under DNA-PK inhibition. Furthermore, the amplified p53 responses were relatively robust. Taken together, our model can faithfully replicate amplified p53 responses under DNA-PK inhibition and provide insights into cell fate decision by manipulating p53 dynamics.

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Section: Discussionsupporting

confidence: 90%

Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

Sun

Shen

2017

Oncotarget

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“…Since the lack of ATM phosphorylation observed in siING3 cells is not observed in siTIP60 cells, our results suggest that ING3-dependent phosphorylation of ATM is independent on TIP60. One hypothesis would be that ING3 has an inhibitory effect on DNA-PKcs activity which itself negatively regulates ATM phosphorylation 48 . Or, the ATM-linked proliferation inhibition observed in siING3 cells could also be due to the activation of the tumor suppressor ARF, as it has been previously described 49 .…”

Section: Discussionmentioning

confidence: 99%

ING3 is required for ATM signaling and DNA repair in response to DNA double strand breaks

et al. 2019

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ING3 (Inhibitor of Growth 3) is a candidate tumor suppressor gene whose expression is lost in tumors such as hepatocellular carcinoma, head and neck squamous cell carcinoma and melanoma. In the present study, we show that ING3-depleted human cells and yeast cells deleted for its ortholog YNG2 are sensitive to DNA damage suggesting a conserved role in response to such stress. In human cells, ING3 is recruited to DNA double strand breaks and is required for ATM activation. Remarkably, in response to doxorubicin, ATM activation is dependent on ING3 but not on TIP60, whose recruitment to DNA breaks also depends on ING3.These events lead to ATM-mediated phosphorylation of NBS1 and the subsequent recruitment of RNF8, RNF168, 53BP1 and BRCA1, which are major mediators of the DNA damage response. Accordingly, upon genotoxic stress, DNA repair by Non Homologous End Joining (NHEJ) or Homologous Recombination (HR) were impaired in absence of ING3. Finally, immunoglobulin Class Switch Recombination (CSR), a physiological mechanism requiring NHEJ repair, was impaired in the absence of ING3. Since deregulation of DNA double strand break repair is associated with genomic instability, we propose a novel function of ING3 as a caretaker tumor suppressor involved in the DNA damage signaling and repair.Finally, we found that ING3 deficiency in B-cells results in decreased Class Switch Recombination (CSR).

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“…Dissociation of Ku70/80 following phosphorylation allows resection to begin, increasing the rate of HR in S phase. DNA-PKcs also regulates HR by modulating the activity of the ATM kinase in response to DNA damage (27). ATM is a master regulator of DNA damage responses, with hundreds of known substrates.…”

Section: Regulation Of Nhejmentioning

confidence: 99%

How cells ensure correct repair of DNA double-strand breaks

Her

Bunting

2018

Journal of Biological Chemistry

238

207

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DNA double-strand breaks (DSBs) arise regularly in cells and when left unrepaired cause senescence or cell death. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are the two major DNA-repair pathways. Whereas HR allows faithful DSB repair and healthy cell growth, NHEJ has higher potential to contribute to mutations and malignancy. Many regulatory mechanisms influence which of these two pathways is used in DSB repair. These mechanisms depend on the cell cycle, post-translational modifications, and chromatin effects. Here, we summarize current research into these mechanisms, with a focus on mammalian cells, and also discuss repair by "alternative end-joining" and single-strand annealing.

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Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM

Cited by 108 publications

References 44 publications

Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

ING3 is required for ATM signaling and DNA repair in response to DNA double strand breaks

How cells ensure correct repair of DNA double-strand breaks

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