ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses

Yang, Jun; Yu, Yingnian; Hamrick, Hope E.; Duerksen-Hughes, Penelope J.

doi:10.1093/carcin/bgg137

Cited by 253 publications

(209 citation statements)

References 124 publications

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“…18 Inhibition of topoisomerase II is responsible for the production of ds breaks on DNA, which are recognized by proteins involved in DNA repair as well as proteins that control cell proliferation and cell death. 19 A major pathway activated by DDR involves the ataxiatelangiectasia mutated (ATM) kinase and the DNA-dependent protein kinase (DNA-PK), both of which are implicated in the induction of the DNA repair. 19 ATM is also important in the induction of the G 1 checkpoint as a result of the activation of the tumor suppressor p53.…”

Section: Discussionmentioning

confidence: 99%

“…19 A major pathway activated by DDR involves the ataxiatelangiectasia mutated (ATM) kinase and the DNA-dependent protein kinase (DNA-PK), both of which are implicated in the induction of the DNA repair. 19 ATM is also important in the induction of the G 1 checkpoint as a result of the activation of the tumor suppressor p53. 20 Previous work from our group showed that PKR is implicated in the phosphorylation and activation of p53 in response to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

et al. 2010

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The eukaryotic cell responds to various forms of environmental stress by adjusting the rates of mRNA translation thus facilitating adaptation to the assaulting stress. One of the major pathways that control protein synthesis involves the phosphorylation of the a-subunit of eukaryotic initiation factor eIF2 at serine 51. Different forms of DNA damage were shown to induce eIF2a phosphorylation by using PERK, GCN2 or PKR. However, the specificity of the eIF2a kinases and the biological role of eIF2a phosphorylation pathway in the DNA damage response (DDR) induced by chemotherapeutics are not known. Herein, we show that PKR is the eIF2a kinase that responds to DDR induced by doxorubicin. We show that activation of PKR integrates two signaling pathways with opposing biological outcomes. More specifically, induction of eIF2a phosphorylation has a cytoprotective role, whereas activation of c-jun N-terminal kinase (JNK) by PKR promotes cell death in response to doxorubicin. We further show that the proapoptotic effects of JNK activation prevail over the cytoprotection mediated by eIF2a phosphorylation. These findings reveal that PKR can be an important inducer of cell death in response to chemotherapies through its ability to act independently of eIF2a phosphorylation. The eukaryotic cell has established intricate mechanisms to cope with environmental stress. It does so by changing protein expression in a manner that promotes adaptation to the assaulting stress. Protein expression within the cell is regulated at the transcriptional, translational and posttranslational levels. Translational control is often used under conditions of cellular stress because it allows immediate and selective changes in protein levels. 1 Translation itself is divided into three distinct phases: initiation, elongation and termination. By far the most explored step is that of initiation, which has been shown to be regulated by different extracellular stimuli. 1 One of the major pathways that control translation initiation is that of the phosphorylation of the a-subunit of translation initiation factor eIF2. 2 Phosphorylation of eIF2a at serine 51 (S51) leads to the inhibition of global protein synthesis providing the cell with the opportunity to elicit adaptive responses not only by saving energy but also by preventing the accumulation of unwanted proteins that could interfere with cellular functions. 1 There are four eIF2a kinases that share a homologous kinase domain (KD) but possess different regulatory domains that enable them to become activated by distinct stimuli. 2 The eIF2a kinases are the heme-regulated inhibitor, which is found mainly in erythroid cells and is activated by heme deficiency; the endoplasmic reticulum (ER)-resident kinase (PERK), which is activated by ER stress and inhibits protein synthesis as part of the unfolded protein response; the general aminoacid nonderepressing kinase 2 (GCN2), which responds to amino-acid deprivation and becomes activated by uncharged tRNA and the RNA-dependent protein kinase PKR, an interfer...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

et al. 2010

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“…Although the R28A mutant could not be stably retained at DNA damage sites, the mutant does not affect the late ATM activation. It is possible that activation of other PI3 kinases such as ATR and DNA-PKcs facilitates the late ATM activation (Yang et al 2003;Stiff et al 2006). However, in the presence of the K160A mutant, the activation of ATM was significantly delayed (Fig.…”

Section: Computational Analysis Of the Par-binding Pockets In The Fhamentioning

confidence: 97%

The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response

et al. 2013

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Poly-ADP-ribosylation is a unique post-translational modification participating in many biological processes, such as DNA damage response. Here, we demonstrate that a set of Forkhead-associated (FHA) and BRCA1 C-terminal (BRCT) domains recognizes poly(ADP-ribose) (PAR) both in vitro and in vivo. Among these FHA and BRCT domains, the FHA domains of APTX and PNKP interact with iso-ADP-ribose, the linkage of PAR, whereas the BRCT domains of Ligase4, XRCC1, and NBS1 recognize ADP-ribose, the basic unit of PAR. The interactions between PAR and the FHA or BRCT domains mediate the relocation of these domain-containing proteins to DNA damage sites and facilitate the DNA damage response. Moreover, the interaction between PAR and the NBS1 BRCT domain is important for the early activation of ATM during DNA damage response and ATM-dependent cell cycle checkpoint activation. Taken together, our results demonstrate two novel PAR-binding modules that play important roles in DNA damage response.

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“…[34][35][36] PI3KKs are activated at the very early stages of DNA damage response and could serve as sensors, as well as initiators, of the ensuing genotoxic stress response. ATM and DNA-PKcs respond to the presence of DSBs, and act during all phases of the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

Nieborowska‐Skorska

Stokłosa²,

Datta³

et al. 2006

Cell Cycle

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BCR/ABL-positive leukemia cells accumulated more replication-dependent DNA doublestrand breaks (DSBs) than normal counterparts after treatment with cisplatin and mitomycin C (MMC, as assessed by pulse field gel electrophoresis (PFGE) and neutral comet assay. In addition, leukemia cells could repair these lesions more efficiently than normal cells and eventually survive genotoxic treatment. Elevated levels of drug-induced DSBs in leukemia cells were associated with higher activity of ATR kinase, and enhanced phosphorylation of histone H2AX on serine 139 (γ-H2AX). γ-H2AX eventually started to disappear in BCR/ABL cells, while continued to increase in parental cells. In addition, the expression and ATR-mediated phosphorylation of Chk1 kinase on serine 345 were often more abundant in BCR/ ABL-positive leukemia cells than normal counterparts after genotoxic treatment. Inhibition of ATR kinase by caffeine but not Chk1 kinase by indolocarbazole inhibitor, SB218078 sensitized BCR/ABL leukemia cells to MMC in a short-term survival assay. Nevertheless, both caffeine and SB218078 enhanced the genotoxic effect of MMC in a long-term clonogenic assay. This effect was associated with the abrogation of transient accumulation of leukemia cells in S and G 2 /M cell cycle phases after drug treatment. In conclusion, ATR -Chk1 axis was strongly activated in BCR/ABL-positive cells and contributed to the resistance to DNA cross-linking agents causing numerous replication-dependent DSBs.

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ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses

Cited by 253 publications

References 124 publications

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

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