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Volumn 10, Issue 2, 1998, Pages 240-247

Cellular responses to DNA damage

Author keywords

[No Author keywords available]

Indexed keywords

CELL DNA;

EID: 0032053790     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(98)80146-4     Document Type: Article
Times cited : (77)

References (43)
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    • of outstanding interest. The activation of c-Abl tyrosine kinase by ionizing radiation is shown to be defective in ATM-deficient mouse embryo fibroblasts, thymocytes and AT patient cells. IR activation of c-Abl is intact in p53-null cells. The coexpression of the ATM PI3K domain with c-Abl leads to the activation of c-Abl tyrosine kinase. Mutant ATM P13K does not activate c-Abl. Finally, IR induces the tyrosine phosphorylation of RNA polymerase II and this does not occur in AT patient cells. These results suggest that ATM may directly phosphorylate c-Abl at Ser465 to activate the tyrosine phosphorylation of RNA polymerase II.
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    • Baskaran, R.1    Wood, L.2    Whitaker, L.3    Canman, C.4    Morgan, S.5    Xu, Y.6    Barlow, C.7    Baltimore, D.8    Wynshaw-Boris, A.9    Kastan, M.10    Wang, J.11
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    • of special interest. An independent study arriving at the same conclusion as Sanchez et al. [17]. RAD53 phosphorylation is linked to the activation of RAD53 kinase activity in this study. Thus, MEC1 and TEL1 are required to activate RAD53 kinase in the DNA damage response.
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    • Rad-dependent response of the Chk1-encoded protein kinase at the DNA damage checkpoint
    • of special interest. This report first describes the Rad3-dependent activation of Chk1 in the DNA damage response. A panel of S. pombe mutants were examined for the activation of Chk1. In addition to Rad3, several other Rad mutants were found to affect the activation of Chk1, indicating that several protein functions are required as upstream regulators of Chk1 activity. A UV repair mutant, however, shows normal activation of Chk1. The repair mutant is hypersensitive to UV, despite the normal checkpoint response. These results confirm that DNA repair and cell-cycle checkpoints are distinct downstream components of the DNA damage response pathways and both DNA repair and cell-cycle checkpoints are essential to surviving DNA damage.
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    • Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation
    • of special interest. This report describes the maintenance of Cdc2 tyrosine phosphorylation in S. pombe treated with UV. The overproduction of Chk1 can cause G2 arrest and this requires Wee1. Chk1 can phosphorylate Wee1 in vitro. UV also induces hyperphosphorylation of Wee1; however, hyperphosphorylated Wee1 is not more active. If tyrosine phosphorylation of Cdc2 is the key to the G2/M checkpoint, Wee1 must be required even if the Wee1 activity itself is not the critical target of the Chk1-regulated pathway.
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    • of special interest. Using a temperature-sensitive Wee1 mutant, this report convincingly demonstrates that radiation-induced G2/M checkpoint can be observed after Wee1 and Mik1 are both inactivated. This result strongly implicated that pre-existing phosphotyrosine on Cdc2 must not be dephosphorylated after DNA damage. In S. pombe, Cdc25 is found to associate with Chk1 and can be phosphorylated by Chk1 in vitro.
    • Furnari B, Thind N, Russell P. Cdc25 mitotic inducer targeted by Chk1 DNA damage checkpoint kinase. of special interest Science. 277:1997;1495-1497 Using a temperature-sensitive Wee1 mutant, this report convincingly demonstrates that radiation-induced G2/M checkpoint can be observed after Wee1 and Mik1 are both inactivated. This result strongly implicated that pre-existing phosphotyrosine on Cdc2 must not be dephosphorylated after DNA damage. In S. pombe, Cdc25 is found to associate with Chk1 and can be phosphorylated by Chk1 in vitro.
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    • of special interest. This report describes the cloning of hChk1. Sequence alignment of human, mouse, Drosophila, Caenorhabditis elegans and yeast Chk1 is shown. The exposure of cells to IR leads to a change in the electrophoretic mobility of hChk1, most likely due to phosphorylation. hChk1 is found to phosphorylate hCDC25A, B and C in vitro. The site of phosphorylation in CDC25C is determined to be Ser216.
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    • Mitotic and G2 checkpoint control: Regulation of 14-3-3 protein binding by phosphorylation of Cdc25c on Serine-216
    • of outstanding interest. This report characterizes the effect of Ser216 phosphorylation on the biochemical and the biological activity of CDC25C. Ser216 is shown to be phosphorylated in S and G2 HeLa cells but not in metaphase-arrested cells: thus, Ser216 phosphorylation is correlated with the activation of CDC25C at metaphase. The overproduction of a Ser216Ala mutant of CDC25C interfered with the replication checkpoint (which ensures that mitosis does not occur until the DNA is replicated) as well as the IR-induced G2 checkpoint. Phosphorylation at Ser216 stimulates the binding of CDC25C to 14-3-3, but has no effect on the CDC25C phosphatase activity. S. pombe Chk1 is shown to phosphorylate CDC25C at Ser216.
    • Peng C, Graves P, Thoma R, Wu Z, Shaw A, Piwnica-Worms H. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25c on Serine-216. of outstanding interest Science. 277:1997;1501-1505 This report characterizes the effect of Ser216 phosphorylation on the biochemical and the biological activity of CDC25C. Ser216 is shown to be phosphorylated in S and G2 HeLa cells but not in metaphase-arrested cells: thus, Ser216 phosphorylation is correlated with the activation of CDC25C at metaphase. The overproduction of a Ser216Ala mutant of CDC25C interfered with the replication checkpoint (which ensures that mitosis does not occur until the DNA is replicated) as well as the IR-induced G2 checkpoint. Phosphorylation at Ser216 stimulates the binding of CDC25C to 14-3-3, but has no effect on the CDC25C phosphatase activity. S. pombe Chk1 is shown to phosphorylate CDC25C at Ser216.
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    • Peng, C.1    Graves, P.2    Thoma, R.3    Wu, Z.4    Shaw, A.5    Piwnica-Worms, H.6
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    • Mdm2 promotes the rapid degradation of p53
    • of special interest. Increased expression of Mdm2 is found to reduce the steady state levels of p53 and decrease the stability of p53 without affecting p53 mRNA levels. This is observed in several different cell types. The precise mechanism of Mdm2-dependent degradation of p53 was not elucidated.
    • Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. of special interest Nature. 387:1997;296-299 Increased expression of Mdm2 is found to reduce the steady state levels of p53 and decrease the stability of p53 without affecting p53 mRNA levels. This is observed in several different cell types. The precise mechanism of Mdm2-dependent degradation of p53 was not elucidated.
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    • Regulation of p53 stability by Mdm2
    • of special interest. This research yielded similar results to those given above in Haupt et al. [27]. The Mdm2-mediated reduction in p53 is inhibited by lactacystin, an inhibitor of proteosomes, suggesting that the Mdm2-p53 complex may be targeted to the proteosomes.
    • Kubbutat M, Jones S, Vousden K. Regulation of p53 stability by Mdm2. of special interest Nature. 387:1997;299-303 This research yielded similar results to those given above in Haupt et al. [27]. The Mdm2-mediated reduction in p53 is inhibited by lactacystin, an inhibitor of proteosomes, suggesting that the Mdm2-p53 complex may be targeted to the proteosomes.
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