Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation. (original) (raw)
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| タイトル: | Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation. |
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| 著者: | Kobayashi, Junya  Kato, Akihiro Ota, YosukeOhba, ReikoKomatsu, Kenshi |
| 著者名の別形: | 小林, 純也 |
| 発行日: | 9-Feb-2010 |
| 出版者: | BioMed Central Ltd |
| 誌名: | Molecular cancer |
| 巻: | 9 |
| 論文番号: | 34 |
| 抄録: | BACKGROUND: MRE11 is an important nuclease which functions in the end-resection step of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). As MRE11-deficient ATLD cells exhibit hyper radio-sensitivity and impaired DSB repair, MRE11 inhibitors could possibly function as potent radio-sensitizers. Therefore, we investigated whether a bisbenzamidine derivative, pentamidine, which can inhibit endoexonuclease activity, might influence DSB-induced damage responses via inhibition of MRE11. RESULTS: We first clarified that pentamidine inhibited MRE11 nuclease activity and also reduced ATM kinase activity in vitro. Pentamidine increased the radio-sensitivity of HeLa cells, suggesting that this compound could possibly influence DNA damage response factors in vivo. Indeed, we found that pentamidine reduced the accumulation of gamma-H2AX, NBS1 and phospho-ATM at the sites of DSBs. Furthermore, pentamidine decreased HR activity in vivo. Pentamidine was found to inhibit the acetylation of histone H2A which could contribute both to inhibition of IR-induced focus formation and HR repair. These results suggest that pentamidine might exert its effects by inhibiting histone acetyltransferases. We found that pentamidine repressed the activity of Tip60 acetyltransferase which is known to acetylate histone H2A and that knockdown of Tip60 by siRNA reduced HR activity. CONCLUSION: These results indicate that inhibition of Tip60 as well as hMRE11 nuclease by pentamidine underlies the radiosensitizing effects of this compound making it an excellent sensitizer for radiotherapy or chemotherapy. |
| 著作権等: | © 2010 Kobayashi et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| URI: | http://hdl.handle.net/2433/129490 |
| DOI(出版社版): | 10.1186/1476-4598-9-34 |
| PubMed ID: | 20144237 |
| 出現コレクション: | 学術雑誌掲載論文等 |
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