論文 - 詳細
| RRC ID | 42571 |
|---|---|
| 著者 | Shiotani B, Kobayashi M, Watanabe M, Yamamoto K, Sugimura T, Wakabayashi K. |
| タイトル | Involvement of the ATR- and ATM-dependent checkpoint responses in cell cycle arrest evoked by pierisin-1. |
| ジャーナル | Mol Cancer Res |
| Abstract |
Pierisin-1 identified from the cabbage butterfly, Pieris rapae, is a novel mono-ADP-ribosylating toxin that transfers the ADP-ribose moiety of NAD at N(2) of dG in DNA. Resulting mono-ADP-ribosylated DNA adducts cause mutations and the induction of apoptosis. However, little is known about checkpoint responses elicited in mammalian cells by the formation of such bulky DNA adducts. In the present study, it was shown that DNA polymerases were blocked at the specific site of mono-ADP-ribosylated dG, which might lead to the replication stress. Pierisin-1 treatment of HeLa cells was found to induce an intra-S-phase arrest through both ataxia telangiectasia mutated (ATM) and Rad3-related (ATR) and ATM pathways, and ATR pathway also contributes to a G(2)-M-phase delay. In the colony survival assays, Rad17(-/-) DT40 cells showed greater sensitivity to pierisin-1-induced cytotoxicity than wild-type and ATM(-/-) DT40 cells, possibly due to defects of checkpoint responses, such as the Chk1 activation. Furthermore, apoptotic 50-kb DNA fragmentation was observed in the HeLa cells, which was well correlated with occurrence of phosphorylation of Chk2. These results thus suggest that pierisin-1 treatment primarily activates ATR pathway and eventually activates ATM pathway as a result of the induction of apoptosis. From these findings, it is suggested that mono-ADP-ribosylation of DNA causes a specific type of fork blockage that induces checkpoint activation and signaling. |
| 巻・号 | 4(2) |
| ページ | 125-33 |
| 公開日 | 2006-2-1 |
| DOI | 10.1158/1541-7786.MCR-05-0104 |
| PII | 4/2/125 |
| PMID | 16513843 |
| MeSH | ADP Ribose Transferases Adenosine Diphosphate Ribose / metabolism* Animals Ataxia Telangiectasia Ataxia Telangiectasia Mutated Proteins Blotting, Western Butterflies / metabolism Cell Cycle / drug effects* Cell Cycle Proteins / antagonists & inhibitors Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Cell Cycle Proteins / physiology* Checkpoint Kinase 1 Checkpoint Kinase 2 Colony-Forming Units Assay DNA / metabolism DNA-Binding Proteins / antagonists & inhibitors DNA-Binding Proteins / genetics DNA-Binding Proteins / physiology* Enzyme Activation Fibroblasts / metabolism Genes, Tumor Suppressor HeLa Cells / drug effects HeLa Cells / metabolism Humans Immunoprecipitation Insect Proteins / pharmacology* Mice Mice, Knockout Phosphorylation Protein Kinases / metabolism Protein Serine-Threonine Kinases / antagonists & inhibitors Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* Protein Serine-Threonine Kinases / physiology* RNA, Small Interfering / pharmacology Signal Transduction Tumor Suppressor Proteins / antagonists & inhibitors Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / physiology* |
| IF | 4.63 |
| 引用数 | 11 |
| WOS 分野 | ONCOLOGY CELL BIOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | HeLa(RCB0007) |