Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair.
Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair.
复制标题
DOI：
10.1093/nar/gkl108
复制
发表时间：
2006
影响因子：
14.9
通讯作者：
Helleday T
中科院分区：
文献类型：
--
作者：
Bryant HE;Helleday T
多聚(ADP-核糖)聚合酶(PARP-1)、ATM和DNA依赖的蛋白激酶(DNA-PK)都参与了对DNA损伤的反应，以激活负责细胞生存的通路。在这里，我们证明了PARP-1−/−细胞对ATM抑制剂KU55933敏感，反之AT细胞对PARP抑制剂4-氨基-1，8-萘二甲酰胺敏感。此外，PARP-1−/−细胞对DNA-PK抑制剂NU7026敏感，DNA-PKcs或Ku80缺陷细胞对PARP抑制剂敏感。我们认为，抑制PARP会导致未解决的自发DNA单链断裂(SSB)增加，从而破坏复制叉并触发同源重组修复(HRR)。我们证明了ATM在PARP抑制后被激活。此外，在ATM抑制的细胞中，PARP抑制剂诱导的HRR被取消，但DNA-PK抑制的细胞不能。ATM和DNA-PK抑制一起对PARP抑制剂的敏感性与单独ATM相同，表明ATM与DNA-PK在折叠叉口存活的途径相同，可能是在非同源末端连接(NHEJ)中。综上所述，我们认为ATM由PARP抑制剂诱导的折叠复制叉子激活，并可能在HRR上游修复某些类型的双链断裂(DSB)中发挥作用。
Poly (ADP-ribose) polymerase (PARP-1), ATM and DNA-dependent protein kinase (DNA-PK) are all involved in responding to DNA damage to activate pathways responsible for cellular survival. Here, we demonstrate that PARP-1−/− cells are sensitive to the ATM inhibitor KU55933 and conversely that AT cells are sensitive to the PARP inhibitor 4-amino-1,8-napthalamide. In addition, PARP-1−/− cells are shown to be sensitive to the DNA-PK inhibitor NU7026 and DNA-PKcs or Ku80 defective cells shown to be sensitive to PARP inhibitors. We believe PARP inhibition results in an increase in unresolved spontaneous DNA single-strand breaks (SSBs), which collapse replication forks and trigger homologous recombination repair (HRR). We show that ATM is activated following inhibition of PARP. Furthermore, PARP inhibitor-induced HRR is abolished in ATM, but not DNA-PK, inhibited cells. ATM and DNA-PK inhibition together give the same sensitivity to PARP inhibitors as ATM alone, indicating that ATM functions in the same pathways as DNA-PK for survival at collapsed forks, likely in non-homologous end joining (NHEJ). Altogether, we suggest that ATM is activated by PARP inhibitor-induced collapsed replication forks and may function upstream of HRR in the repair of certain types of double-strand breaks (DSBs).
登录
查看更多内容
影响因子：
3.5
作者：
Bolderson, E;Scorah, J;Meuth, M
通讯作者：
Meuth, M
影响因子：
13.8
作者：
LINDAHL, T;SATOH, MS;KLUNGLAND, A
通讯作者：
KLUNGLAND, A
影响因子：
3.7
作者：
Kurose, A;Tanaka, T;Darzynkiewicz, Z
通讯作者：
Darzynkiewicz, Z
替莫唑胺诱导的细胞毒性的增强：对聚（ADP-核糖）聚合酶抑制剂的生物学作用的比较研究。
影响因子：
8.8
作者：
Boulton, S;Pemberton, L C;Porteous, J K;Curtin, N J;Griffin, R J;Golding, B T;Durkacz, B W
通讯作者：
Durkacz, B W
影响因子：
6.2
作者：
Curtin, Nicola J.
通讯作者：
Curtin, Nicola J.