Foundations in Cancer Research p53 and ATM: Cell Cycle, Cell Death, and Cancer

Morgan, Susan E.; Kastan, Michael B.

doi:10.1016/s0065-230x(08)60095-0

Cited by 285 publications

(158 citation statements)

References 160 publications

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“…Consistent with this, Western analysis demonstrated the activation of ATM in the PR-Set7 shRNA cells, which is known to occur during S phase and G 2 /M arrests ( Fig. 3E) (41). Therefore, our findings show that the lack of PR-Set7 and monomethylated H4K20 results in a cell cycle arrest or delay with cells amassing in S phase and G 2 /M.…”

Section: Global Changes In H4k20 Methylation Occur During Cell Cyclesupporting

confidence: 87%

Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability

Houston

McManus

Adams

et al. 2008

Journal of Biological Chemistry

142

169

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Histone-modifying enzymes play a critical role in modulating chromatin dynamics. In this report we demonstrate that one of these enzymes, PR-Set7, and its corresponding histone modification, the monomethylation of histone H4 lysine 20 (H4K20), display a distinct cell cycle profile in mammalian cells: low at G 1 , increased during late S phase and G 2 , and maximal from prometaphase to anaphase. The lack of PR-Set7 and monomethylated H4K20 resulted in a number of aberrant phenotypes in several different mammalian cell types. These include the inability of cells to progress past G 2 , global chromosome condensation failure, aberrant centrosome amplification, and substantial DNA damage. By employing a catalytically dead dominant negative PR-Set7 mutant, we discovered that its mono-methyltransferase activity was required to prevent these phenotypes. Importantly, we demonstrate that all of the aberrant phenotypes associated with the loss of PR-Set7 enzymatic function occur independently of p53. Collectively, our findings demonstrate that PR-Set7 enzymatic activity is essential for mammalian cell cycle progression and for the maintenance of genomic stability, most likely by monomethylating histone H4K20. Our results predict that alterations of this pathway could result in gross chromosomal aberrations and aneuploidy.Dynamic alterations in chromatin structure are modulated, in part, by the post-translational modifications of the DNAassociated histone proteins. Specialized chromatin-modifying enzymes can phosphorylate, acetylate, ubiquitylate, or methylate specific amino acids within certain histones, and each of these modifications are associated with distinct biological events (1). One of the first histone modifications to be identified nearly forty-five years ago was the methylation of histone H4 lysine 20 (H4K20) 4 (2). Earlier biochemical studies linked H4K20 methylation to diverse biological events including transcriptional regulation, chromatin compaction, cell division, and the formation of heterochromatin (3-9). Importantly, it was also found that H4K20 is differentially methylated in vivo and therefore can be either mono-, di-, or trimethylated (10). Together, these findings strongly suggest that different methylated states of H4K20 may be involved in distinct biological processes, similar to what is observed for the various methylated states of histone H3 lysine 4 and 9 methylation (11, 12).Increasing evidence indicates that certain enzymes are responsible for the specific degree of histone lysine methylation (13). For example, the mono-and dimethylation of histone H3 lysine 9 in humans is mediated by the G9a enzyme, whereas trimethylation is mediated by the SUV39H1 enzyme (14,15). Similarly, the Suv4 -20 enzymes are responsible for di-and trimethylation in mammals (16,17). Trimethylated H4K20 is associated with repressed chromatin because it is targeted to constitutive heterochromatin, various repetitive elements, and imprinting control regions (16,18,19). Dimethylated H4K40 is more widely distributed within...

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Section: Global Changes In H4k20 Methylation Occur During Cell Cyclesupporting

confidence: 87%

Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability

Houston

McManus

Adams

et al. 2008

Journal of Biological Chemistry

142

169

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“…DNA-PK is a member of the PI3-kinase family; and together with other members of the same family, such as ATM (the protein deficient in the human neurodegenerative and cancer predisposition condition ataxia telangiectasia) and the human AT-related (ATR/FRAP-related) protein, it has been implicated in controlling transcription, the cell cycle and/or genomic instability in organisms ranging from yeast to humans. [23][24][25] DNA-PK has been implicated in the DNA damage signaltransduction pathway, being able to phosphorylate in vitro p53 26 and in vivo Replication protein A. 27 A similar degree of ET-743-increased sensitivity (2-fold) has been observed in ATM null cells.…”

Section: Discussionmentioning

confidence: 86%

Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways

et al. 2001

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The cytotoxic activity of ecteinascidin 743 (ET-743), a natural product derived from the marine tunicate Ecteinascidia turbinata that exhibits potent anti-tumor activity in pre-clinical systems and promising activity in phase I and II clinical trials, was investigated in a number of cell systems with well-defined deficiencies in DNA-repair mechanisms. ET-743 binds to N2 of guanine in the minor groove, but its activity does not appear to be related to DNA-topoisomerase I poisoning as the drug is equally active in wild-type yeast and in yeast with a deletion in the DNA-topoisomerase I gene. Defects in the mismatch repair pathway, usually associated with increased resistance to methylating agents and cisplatin, did not affect the cytotoxic activity of ET-743. However, ET-743 did show decreased activity (from 2-to 8-fold) in nucleotide excision repair ( Ecteinascidin 743 (ET-743) is a natural product derived from the marine tunicate Ecteinascidia turbinata, selected for its significant anti-tumor activity in different in vitro and in vivo models. [1][2][3] Currently, ET-743 is undergoing phase II clinical trials after having shown activity in phase I clinical studies with responses observed in different human tumors, including soft tissue sarcoma, osteosarcoma, melanoma and breast cancer. 4,5 The mechanism of action of ET-743 has yet to be fully defined, but DNA appears to be the primary target. Indeed, it has been shown to bind in the minor groove of DNA and to alkylate the N2 position of guanine with some degree of specificity. 6,7 Such ET-743 minor-groove alkylation induces a bend in the DNA helix toward the major groove, a finding not common to the other minor groove-alkylating agents, which bend DNA into the minor groove. 8 No single-strand breaks, double-strand breaks or DNAprotein cross-links could be found by alkaline elution in cells exposed to IC 50 concentrations of ET-743. 9 However, Takebayashi et al. 10 showed that ET-743 was able to induce DNA-topoisomerase I cross-linking but that high concentrations were required to produce the effect.To provide some insight into the mechanism of action of ET-743, we have evaluated its cytotoxic activity using a panel of different cellular systems characterized by well-defined deficiencies in different mammalian repair pathways. Our data indicate that ET-743 has a unique mechanism of interaction with DNA. MATERIAL AND METHODS Cells and drugsYeast strains and the isogenic derivatives CY2823 (⌬rad52) and CY2278 (⌬topI) (kindly provided by Dr. M. Lopes, Instituto F.I.R.C. di Oncologia Molecolare, Milan, Italy) were grown in YPD plates (1% yeast extract, 2% bacto-peptone, 2% glucose) with or without the drugs.The Chinese hamster ovary (CHO) parental cell line CHO-AA8 and the UV-sensitive DNA repair-deficient mutant cell lines CHO-UV23, CHO-UV61 and CHO-UV96 (hereafter named UV23, UV61 and UV96) 11 were kindly provided by Dr. M. Stefanini (CNR IGBE, Pavia, Italy). The UV96 cell line was transfected by the calcium phosphate technique using 10 g of a CMV-ERCC1 plasmid enc...

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“…This observation indicates that MMTV-Aurora-A mice developed mammary tumors at higher frequency after they were continuously mated perhaps due to exposure of increased levels of estrogen. p53 is a well-known tumor suppressor gene that is mutated in approximately 50% of all human tumors (Morgan and Kastan, 1997). Aurora kinase A is a key regulatory component of the p53 pathway as overexpression of Aurora kinase degrades p53, leading to downregulation of checkpoint-response pathways and facilitating oncogenic transformation of cells .…”

Section: Aurora-a Induces Mammary Tumor Formation X Wang Et Almentioning

confidence: 99%

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

et al. 2006

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Foundations in Cancer Research p53 and ATM: Cell Cycle, Cell Death, and Cancer

Cited by 285 publications

References 160 publications

Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability

Catalytic Function of the PR-Set7 Histone H4 Lysine 20 Monomethyltransferase Is Essential for Mitotic Entry and Genomic Stability

Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

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