The DNA-dependent protein kinase (DNA-PK): More than just a case of making ends meet?

Hill, Richard; Lee, Patrick W.K.

doi:10.4161/cc.9.17.13043

Cited by 91 publications

(87 citation statements)

References 126 publications

(159 reference statements)

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“…ATM kinase activation is primarily stimulated by blunt double-stranded DNA (dsDNA) ends such as the DNA double-strand breaks (DSBs) incurred through ␥-irradiation (3), whereas ATR activation is most responsive to single-stranded DNA (ssDNA) like that presented by stalled DNA replication intermediates or resected DSB ends (4). DNA-PK is a critical participant in the non-homologous end-joining pathway for repair of V(D)J recombination-induced DSBs but is also thought to serve a vital DNA repair function during genotoxic stress DDRs (5). However, growing evidence suggests that extensive cross-talk between the DNA damage-responsive phosphoinositide 3-kinase-related kinases exists, the summation of which determines cell fate (4 -6).…”

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confidence: 99%

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Elevated Cyclin G2 Expression Intersects with DNA Damage Checkpoint Signaling and Is Required for a Potent G2/M Checkpoint Arrest Response to Doxorubicin

Zimmermann

Arachchige-Don

Donaldson

et al. 2012

Journal of Biological Chemistry

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Background: DNA damage triggers cell cycle checkpoints to halt cell division ahead of DNA repair. Results: Ectopic cyclin G2 (CycG2) induces a Chk2-dependent cell cycle arrest, and depletion of endogenous CycG2 attenuates doxorubicin-induced G 2 /M-phase cell cycle arrest. Conclusion: CycG2 influences checkpoint signaling and is required for G 2 /M arrest responses to genotoxic stress. Significance: Proper checkpoint function is important for genomic integrity and tumor suppression.

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confidence: 99%

“…If damage to chromosomal DNA is not corrected, these insults will lead to genomic instability and cancer. The presence of a lesion is relayed within minutes of the genomic insult through DNA damage response (DDR) 5 signal-transduction pathways. Signaling cascades including sensor, transducer, and effector proteins carry out a particular response (e.g.…”

mentioning

confidence: 99%

Elevated Cyclin G2 Expression Intersects with DNA Damage Checkpoint Signaling and Is Required for a Potent G2/M Checkpoint Arrest Response to Doxorubicin

Zimmermann

Arachchige-Don

Donaldson

et al. 2012

Journal of Biological Chemistry

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“…This is consistent with the increasing evidence that DNA-PK has further roles than providing a scaffold where DNA ligation takes place. 13 In fact, DNA-PK has been shown to participate in cell fate during events which favor cell death by its linkage to cellular death machinery, and is indispensable for DSBs and V(D)J recombination through non-homologous end joining repair mechanisms. 13 Two other DDR kinases, specifically ATM and ATR, were shown to be activated in response to TPEN.…”

Section: Discussionmentioning

confidence: 99%

“…13 In fact, DNA-PK has been shown to participate in cell fate during events which favor cell death by its linkage to cellular death machinery, and is indispensable for DSBs and V(D)J recombination through non-homologous end joining repair mechanisms. 13 Two other DDR kinases, specifically ATM and ATR, were shown to be activated in response to TPEN. These two PI3K-like kinases are part of pathways that lead to the activation of substrates involved in DNA repair, checkpoint signaling and cell fate determination.…”

Section: Discussionmentioning

confidence: 99%

“…12 DNA-PK, a nuclear serine/threonine kinase, is another DNA damage sensor that can detect double strand breaks (DSBs), and elicit non homologous end joining repair mechanisms. 13 If the damage is excessive or DNA repair is ineffective, then activation of cell death is the normal physiological response. 12 Although TPEN has been found to inhibit proliferation and induce apoptosis in many cell systems including lymphocytes, 14 epithelial cells, 15 hepatocytes, 16 breast cancer, 17 HT-29 colorectal cancer, 18,19 splenocytes, ovarian cancer, prostate cancer, 20 and pancreatic cancer, 21 its DNA damage potential and mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells

Rahal

Fatfat

Hankache

et al. 2016

Cancer Biology & Therapy

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Recently, we showed that the metal chelator TPEN targets colon cancer cells through redox cycling of copper. Here, we studied the DNA damage potential of TPEN and deciphered the role of Chk1, ATM and DNA-PK in TPEN-induced toxicity in 3 human colon cancer cell lines, HCT116, SW480 and HT29. We also investigated the role of reactive oxygen species (ROS) in TPEN-induced DNA damage. TPEN reduced cell viability in a dose-and time-dependent manner. Cytotoxicity was associated with significant DNA damage and higher expression of g-H2AX protein and activation of ATM/ATR signaling pathway. Cell death by TPEN was dependent on ROS generation as evidenced by the reversal of cell viability, and DNA damage and the abrogation of g-H2AX levels in the presence of antioxidants. Treatment with antioxidants, however, failed to reverse cytotoxicity at high TPEN concentrations (10mM). TPEN-induced cell death was also dependent on the redox cycling of copper since the copper chelator neocuproine inhibited DNA damage and reduced pChk1, g-H2AX, and ATM protein expression. Cell death by low TPEN concentrations, involved ATM/ATR signaling in all 3 cell lines, since pre-incubation with specific inhibitors of ATM and DNA-PK led to the recovery of cells from TPEN-induced DNA damage. In addition, siRNA silencing of Chk1, DNA-PK and ATM abrogated the expression of g-H2AX and reversed cell death, suggesting that Chk1 and DNA-PK mediate TPEN-induced cytotoxicity in colon cancer cells. This study shows for the first time the involvement of Chk1, DNA-PK and ATM in TPEN-induced DNA damage and confirms our previous findings that ROS generation and the redox cycling of copper in response to TPEN are the main mechanisms by which this compound induces cell death in human colon cancer cells. Inhibition of ATM or DNA-PK did not reverse cytotoxicity at high TPEN concentrations that cause excessive levels of ROS and irreversible cellular damage.Abbreviations: ROS, reactive oxygen species; XIAP, X-linked inhibitor of apoptosis; DNA-PK, DNA-dependent protein kinase; ATM, ataxia telangiectasia mutated; ATR, serine/threonine protein kinase ataxia telangiectasia; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DCFH, 2 0 ,7 0 -Dichlorofluorescin diacetate; NAC, N-acetyL-cysteine; CAT, catalase; DSB, double strand break; SSB, single strand break; Neo, neocuproine; PI, propidium iodide; DDR, DNA damage response

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Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

et al. 2020

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Early detection of infectious nucleic acids released from invading pathogens by the innate immune system is critical for immune defense. Detection of these nucleic acids by host immune sensors and regulation of DNA sensing pathways have been significant interests in the past years. Here, current understandings of evolutionarily conserved DNA sensing cyclic GMP‐AMP (cGAMP) synthase (cGAS) are highlighted. Precise activation and tight regulation of cGAS are vital in appropriate innate immune responses, senescence, tumorigenesis and immunotherapy, and autoimmunity. Hence, substantial insights into cytosolic DNA sensing and immunotherapy of indispensable cytosolic sensors have been detailed to extend limited knowledge available thus far. This Review offers a critical, in‐depth understanding of cGAS regulation, cytosolic DNA sensing, and currently established therapeutic approaches of essential cytosolic immune agents for improved human health.

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The DNA-dependent protein kinase (DNA-PK): More than just a case of making ends meet?

Cited by 91 publications

References 126 publications

Elevated Cyclin G2 Expression Intersects with DNA Damage Checkpoint Signaling and Is Required for a Potent G2/M Checkpoint Arrest Response to Doxorubicin

Elevated Cyclin G2 Expression Intersects with DNA Damage Checkpoint Signaling and Is Required for a Potent G2/M Checkpoint Arrest Response to Doxorubicin

Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

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