Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation.
Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation.
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DOI：
10.1186/1476-4598-9-34
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发表时间：
2010-02-09
期刊：
影响因子：
37.3
通讯作者：
Komatsu K
中科院分区：
文献类型：
--
作者：
Kobayashi J;Kato A;Ota Y;Ohba R;Komatsu K
MRE 11是一种重要的核酸酶，其在DNA双链断裂（DSB）的同源重组（HR）修复的末端切除步骤中起作用。由于MRE 11缺陷型ATLD细胞表现出超辐射敏感性和受损的DSB修复，MRE 11抑制剂可能作为有效的辐射增敏剂发挥作用。因此，我们研究了可以抑制内切核酸酶活性的双苯甲脒衍生物喷他脒是否可能通过抑制MRE 11来影响DSB诱导的损伤反应。我们首先阐明，戊烷脒抑制MRE 11核酸酶活性，也降低ATM激酶活性在体外。Pentamidine可增加HeLa细胞的辐射敏感性，提示该化合物可能影响体内DNA损伤反应因子。事实上，我们发现喷他脒减少了γ-H2 AX、NBS 1和磷酸-ATM在DSB位点的积累。此外，喷他脒降低HR活动在体内。发现喷他脒抑制组蛋白H2 A的乙酰化，这可能有助于抑制IR诱导的病灶形成和HR修复。这些结果表明，喷他脒可能通过抑制组蛋白乙酰转移酶发挥其作用。我们发现，喷他脒抑制Tip 60乙酰转移酶的活性，已知Tip 60乙酰转移酶使组蛋白H2 A乙酰化，并且通过siRNA敲低Tip 60降低HR活性。这些结果表明，戊烷脒对Tip 60以及hMRE 11核酸酶的抑制是该化合物的放射增敏作用的基础，使其成为放射治疗或化学治疗的优异增敏剂。
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. 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 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. 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.
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影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
DOI：
10.1006/bbrc.1999.1737
发表时间：
1999-11-30
影响因子：
3.1
作者：
Ito, A;Tauchi, H;Komatsu, K
通讯作者：
Komatsu, K
影响因子：
64.5
作者：
Bassing, CH;Suh, H;Alt, FW
通讯作者：
Alt, FW
影响因子：
16
作者：
Downs, JA;Allard, S;Côté, J
通讯作者：
Côté, J
影响因子：
9.2
作者：
Paull, TT;Rogakou, EP;Bonner, WM
通讯作者：
Bonner, WM