Hyperactivation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage

Finzel, Ana; Grybowski, Andrea; Strasen, Jette; Cristiano, Elena; Loewer, Alexander

doi:10.1091/mbc.e16-01-0032

Cited by 53 publications

(79 citation statements)

References 36 publications

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“…Consistent with our observations, increased global phosphorylation of H2AX as well as higher enrichment of γH2AX at AsiSI-induced DSBs have been observed in U2OS cells upon DNA-PKi treatment (Caron et al, 2015). Hyperactivation of ATM upon DNA-PKcs inhibition is also reported in A549 and MCF10A cells after IR treatment (Finzel et al, 2016). Notably, this effect was not observed when the NHEJ pathway was inhibited by DNA Ligase IV inhibitor, suggesting that an increase in DSBs alone is not sufficient for ATM hyperactivation upon DNA-PKcs inhibition (Finzel et al, 2016).…”

Section: Resultsmentioning

confidence: 89%

“…Hyperactivation of ATM upon DNA-PKcs inhibition is also reported in A549 and MCF10A cells after IR treatment (Finzel et al, 2016). Notably, this effect was not observed when the NHEJ pathway was inhibited by DNA Ligase IV inhibitor, suggesting that an increase in DSBs alone is not sufficient for ATM hyperactivation upon DNA-PKcs inhibition (Finzel et al, 2016). Taken together, these results suggest that DNA-PKcs negatively regulates ATM activation upon DNA damage in mammalian cells.…”

Section: Resultsmentioning

confidence: 89%

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

et al. 2017

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SUMMARY Ataxia-Telangiectasia Mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. We characterize several phosphorylation sites in ATM that are targets of DNA-PKcs and show that phospho-mimetic mutations at these residues significantly inhibit ATM activity and impair ATM signaling upon DNA damage. In contrast, phospho-blocking mutations at one cluster of sites increase the frequency of apoptosis during normal cell growth. DNA-PKcs, which is integral to the non-homologous end joining pathway, thus negatively regulates ATM activity through phosphorylation of ATM. These observations illuminate an important regulatory mechanism for ATM that also controls DNA repair pathway choice.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 89%

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

et al. 2017

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“…More dynamical p53 patterns have been identified depending on the radiation type and dose [10, 13, 14]. A most recent finding by Finzel et al has demonstrated a novel p53 dynamics in response to DNA damage [15]. Their study argues that ATR or DNA-PK alone could compensate for the deficiency in the other two PI3K-like members and retain regular p53 dynamics.…”

Section: Introductionmentioning

confidence: 99%

“…Their study argues that ATR or DNA-PK alone could compensate for the deficiency in the other two PI3K-like members and retain regular p53 dynamics. Instead, in the absence of DNA-PK, p53 reacts more strongly to ATM mediated phosphorylation with escalated first pulses [15]. ATM is hyper-activated when catalytic DNA-PK activity is blocked, implying that DNA-PK may inhibit ATM kinase activity [15, 16].…”

Section: Introductionmentioning

confidence: 99%

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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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Photobiomodulation effects on mRNA levels from genomic and chromosome stabilization genes in injured muscle

Trajano

Sergio

et al. 2018

Lasers Med Sci

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Muscle injuries are the most prevalent type of injury in sports. A great number of athletes have relapsed in muscle injuries not being treated properly. Photobiomodulation therapy is an inexpensive and safe technique with many benefits in muscle injury treatment. However, little has been explored about the infrared laser effects on DNA and telomeres in muscle injuries. Thus, the aim of this study was to evaluate photobiomodulation effects on mRNA relative levels from genes related to telomere and genomic stabilization in injured muscle. Wistar male rats were randomly divided into six groups: control, laser 25 mW, laser 75 mW, injury, injury laser 25 mW, and injury laser 75 mW. Photobiomodulation was performed with 904 nm, 3 J/cm at 25 or 75 mW. Cryoinjury was induced by two applications of a metal probe cooled in liquid nitrogen directly on the tibialis anterior muscle. After euthanasia, skeletal muscle samples were withdrawn and total RNA extracted for evaluation of mRNA levels from genomic (ATM and p53) and chromosome stabilization (TRF1 and TRF2) genes by real-time quantitative polymerization chain reaction. Data show that photobiomodulation reduces the mRNA levels from ATM and p53, as well reduces mRNA levels from TRF1 and TRF2 at 25 and 75 mW in injured skeletal muscle. In conclusion, photobiomodulation alters mRNA relative levels from genes related to genomic and telomere stabilization in injured skeletal muscle.

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Hyperactivation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage

Cited by 53 publications

References 36 publications

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

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

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

Photobiomodulation effects on mRNA levels from genomic and chromosome stabilization genes in injured muscle

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