Poly(ADP-ribose) glycohydrolase silencing protects against H2O2-induced cell death
Poly(ADP-ribose) glycohydrolase silencing protects against H2O2-induced cell death
复制标题
DOI：
10.1042/bj20051696
复制
发表时间：
2006-06-15
影响因子：
4.1
通讯作者：
Malanga, Maria
中科院分区：
文献类型：
--
作者：
Blenn, Christian;Althaus, Felix R.;Malanga, Maria
PAR [poly(ADP-ribose)]是真核细胞中多蛋白复合物的结构和调控成分。在遗传毒性应激条件下，PAR分解代谢加速，这主要归因于PARG （PAR糖水解酶）的活性。为了克服PARG基因敲除小鼠的早期胚胎致死性，并进一步了解PARG的生物学功能，我们使用了RNA干扰方法。我们发现，只要10%的PARG蛋白就足以保证基本的细胞功能：通过几轮传代培养，PARG沉默的小鼠和人类细胞正常增殖，并且它们能够修复亚致死剂量H2O2诱导的DNA损伤。然而，高浓度H2O2 （0.05-1 mM）处理后细胞存活率增加。事实上，与野生型细胞相比，parg沉默的细胞对氧化诱导的凋亡更有抵抗力，同时在药物治疗的早期阶段表现出延迟的PAR降解和超过15米的adp核糖聚合物的短暂积累。DNA烷基化剂n -甲基-n '-硝基-n -亚硝基胍的反应没有差异，这表明PARG特异性参与了细胞对DNA氧化损伤的反应。
PAR [poly(ADP-ribose)] is a structural and regulatory component of multiprotein complexes in eukaryotic cells. PAR catabolism is accelerated under genotoxic stress conditions and this is largely attributable to the activity of a PARG (PAR glycohydrolase). To overcome the early embryonic lethality of parg-knockout mice and gain more insights into the biological functions of PARG, we used an RNA interference approach. We found that as little as 10% of PARG protein is sufficient to ensure basic cellular functions: PARG-silenced murine and human cells proliferated normally through several subculturing rounds and they were able to repair DNA damage induced by sublethal doses of H2O2. However, cell survival following treatment with higher concentrations of H2O2 (0.05-1 mM) was increased. In fact, PARG-silenced cells were more resistant than their wild-type counterparts to oxidant-induced apoptosis while exhibiting delayed PAR degradation and transient accumulation of ADP-ribose polymers longer than 15-mers at early stages of drug treatment. No difference was observed in response to the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine, suggesting a specific involvement of PARG in the cellular response to oxidative DNA damage.