Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation

Molecular Cancer

Research

Akihiro Kato¹  Yosuke Ota¹  Kenshi Komatsu¹  Junya Kobayashi¹  Reiko Ohba² 

[1] Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, 606-8501, Kyoto, Japan;Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, 606-8501, Kyoto, Japan;National Institute of Genetics, Yata 1111, Mishima, 411-8540, Sizuoka, Japan;

关键词: Pentamidine;    Focus Formation;    Homologous Recombination Repair;    Anacardic Acid;    Homologous Recombination Activity;   

DOI  :  10.1186/1476-4598-9-34

 received in 2009-11-05, accepted in 2010-02-09,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundMRE11 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.ResultsWe 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 γ-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.ConclusionThese 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.

【 授权许可】

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© Kobayashi et al; licensee BioMed Central Ltd. 2010