Turning off the G2 DNA damage checkpoint

Calonge, Teresa M.; O’Connell, Matthew J.

doi:10.1016/j.dnarep.2007.07.017

Cited by 32 publications

(31 citation statements)

References 47 publications

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“…Because the stability of Rad17 is regulated by proteasome-dependent protein degradation during checkpoint recovery (1)(2)(3)21), the involvement of proteasomal protein degradation was examined. Exposure to the proteasome inhibitor MG132 did not affect the increase in Rad17 phosphorylation induced by SU6656 (Fig.…”

Section: Sfk Activity Is Required For G 2 Dna Damage Checkpointmentioning

confidence: 99%

“…Following checkpoint activation, several protein phosphatases and ubiquitin ligases target the activated checkpoint proteins including Rad17 (21), Claspin (22)(23)(24), and Chk1 (25)(26)(27)(28)(29)(30). The direct dephosphorylation and degradation of checkpoint proteins promote the termination of checkpoint signaling (1)(2)(3).…”

mentioning

confidence: 99%

“…The termination or silencing of checkpoint signaling is also an active process that involves dephosphorylation and proteasomal degradation of checkpoint proteins; however, except for the direct reversal of phosphorylation or removal of the activated checkpoint proteins, very little is known about the signal transduction pathway that is triggered by the completion of DNA repair to initiate the termination of checkpoint signaling. Currently the disappearance of DNA lesions is considered to bring about the end of the activation of the most upstream components of the DNA damage checkpoint, namely the sensors that detect DNA lesions (1)(2)(3).…”

mentioning

confidence: 99%

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Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Fukumoto

Morii

Miura

et al. 2014

Journal of Biological Chemistry

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Background: Once DNA repair is completed, the DNA damage checkpoint is terminated, and the cell cycle is resumed. Results: Src inhibition induced a delay in G 2 checkpoint recovery and persistent ATR-Chk1 activation. Conclusion: Src inhibits ATR signaling to promote recovery from G 2 checkpoint arrest. Significance: Src sends a termination signal between the completion of DNA repair and the initiation of checkpoint termination.

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Section: Sfk Activity Is Required For G 2 Dna Damage Checkpointmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Fukumoto

Morii

Miura

et al. 2014

Journal of Biological Chemistry

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Section: Introductionmentioning

confidence: 99%

“…Recovery from the checkpoint arrest requires Chk1 dephosphorylation, which in S. pombe is catalyzed by the type 1 phosphatase Dis2 (den . This and additional phosphatases have been implicated in the inactivation of human Chk1, as have additional mechanisms including ubiquitin-dependent proteolysis (Calonge and O'Connell, 2008).Molecular details of how the phosphorylation of the C-terminal domain activates the N-terminal kinase domain are poorly understood, though are clearly important to delineate. Structural studies of human Chk1 showed the kinase domain to be in an open conformation (Chen et al, 2000); that is, this domain does not require activating phosphorylation that is commonplace in many protein kinases.…”

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Regulation of Chk1 by Its C-terminal Domain

Kosoy

O’Connell

2008

MBoC

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Chk1 is a protein kinase that is the effector molecule in the G2 DNA damage checkpoint. Chk1 homologues have an N-terminal kinase domain, and a C-terminal domain of ϳ200 amino acids that contains activating phosphorylation sites for the ATM/R kinases, though the mechanism of activation remains unknown. Structural studies of the human Chk1 kinase domain show an open conformation; the activity of the kinase domain alone is substantially higher in vitro than full-length Chk1, and coimmunoprecipitation studies suggest the C-terminal domain may contain an autoinhibitory activity. However, we show that truncation of the C-terminal domain inactivates Chk1 in vivo. We identify additional mutations within the C-terminal domain that activate ectopically expressed Chk1 without the need for activating phosphorylation. When expressed from the endogenous locus, activated alleles show a temperature-sensitive loss of function, suggesting these mutations confer a semiactive state to the protein. Intragenic suppressors of these activated alleles cluster to regions in the catalytic domain on the face of the protein that interacts with substrate, suggesting these are the regions that interact with the C-terminal domain. Thus, rather than being an autoinhibitory domain, the C-terminus of Chk1 also contains domains critical for adopting an active configuration. INTRODUCTIONDNA damage checkpoints halt cell cycle progression to allow time for the repair machinery to correct the lesion. The ultimate targets of these checkpoints are the cyclin-dependent kinases that promote the transition from G1 into S-phase, and from G2 in to mitosis O'Connell and Cimprich, 2005). Two major effectors of the DNA damage checkpoints are the tumor suppressor and transcription factor p53, and the protein serine/threonine kinase Chk1. The importance of checkpoints in genome integrity is highlighted by the frequent inactivation of p53 signaling in tumors, leading to G1/S checkpoint defects and a blockade to apoptosis (Giono and Manfredi, 2006). Conversely, Chk1 and its upstream regulators, which control the G2 DNA damage checkpoint, are rarely (if ever) mutated in tumors, suggesting this pathway may be essential for cancer cell viability. Indeed, inhibition or ablation of Chk1 greatly sensitizes p53 mutant tumor cells to genotoxic therapies (Suganuma et al., 1999;Jackson et al., 2000;Koniaras et al., 2001;Macip et al., 2006). Although Chk1 is essential for embryonic development in the mouse (Liu et al., 2000), this may not be the case for most cells in adult tissues. Therefore, there is intense interest in developing specific Chk1 inhibitors for cancer chemotherapy (Garber, 2005).The G2 DNA damage checkpoint is highly conserved in evolution, and model systems, such as the fission yeast Schizosaccharomyces pombe, have been invaluable in dissecting this signaling pathway. On detection of DNA damage, several protein complexes cooperate to ensure Chk1 activation, leading to a 5-10-fold increase over its basal activity (Capasso et al., 2002;Harvey et al., 2004;Lat...

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Imatinib inhibits inactivation of the ATM/ATR signaling pathway and recovery from adriamycin/doxorubicin‐induced DNA damage checkpoint arrest

Morii

Fukumoto

Kubota

et al. 2015

Cell Biology International

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The DNA damage checkpoint arrests cell cycle progression to allow time for DNA repair. After completion of DNA repair, checkpoint activation is terminated, and cell cycle progression is resumed in a process called checkpoint recovery. The activation of the checkpoint has been studied in depth, but little is known about recovery from the DNA damage checkpoint. Recently we showed that Src family kinases promote recovery from the G2 DNA damage checkpoint. Here we show that imatinib inhibits inactivation of ATM/ATR signaling pathway to suppress recovery from Adriamycin/doxorubicin-induced DNA damage checkpoint arrest. Imatinib and pazopanib, two distinct inhibitors of PDGFR/c-Kit family kinases, delayed recovery from checkpoint arrest and inhibited the subsequent S-G2-M transition after Adriamycin exposure. By contrast, imatinib and pazopanib did not delay the recovery from checkpoint arrest in the presence of an ATM/ATR inhibitor caffeine. Consistently, imatinib induced a persistent activation of ATR-Chk1 signaling. By the way, the maintenance of G2 checkpoint arrest is largely dependent on ATR-Chk1 signaling. However, unlike Src inhibition, imatinib did not delay the recovery from checkpoint arrest in the presence of an ATM inhibitor KU-55933. Furthermore, imatinib induced a persistent activation of ATM-KAP1 signaling, and a possible involvement of imatinib in an ATM-dependent DNA damage response is suggested. These results reveal that imatinib inhibits recovery from Adriamycin-induced DNA damage checkpoint arrest in an ATM/ATR-dependent manner and raise the possibility that imatinib may inhibit resumption of tumor proliferation after chemo- and radiotherapy.

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Turning off the G2 DNA damage checkpoint

Cited by 32 publications

References 47 publications

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Regulation of Chk1 by Its C-terminal Domain

Imatinib inhibits inactivation of the ATM/ATR signaling pathway and recovery from adriamycin/doxorubicin‐induced DNA damage checkpoint arrest

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