PARG dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments different cell death pathways.
PARG dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments different cell death pathways.
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DOI：
10.1038/cddis.2013.133
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发表时间：
2013-06-06
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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聚ADP核糖水解酶（Poly（ADP-ribose）glycohydrolase，PARG）是降解聚ADP核糖的主要酶。PARG功能障碍使细胞对烷化剂敏感并诱导细胞死亡;然而，这种作用的细节尚未完全阐明。在此，我们使用烷化剂甲磺酸甲酯（MMS）、Parg−/−小鼠ES细胞和人癌细胞系，研究了PARG缺陷导致不同细胞类型细胞死亡的机制。Parg−/−小鼠ES细胞表现出增加的γ-H2 AX水平，这是DNA双链断裂（DSB）的标志物，聚（ADP-核糖）的积累，p53网络激活和S期阻滞。Parg−/−小鼠ES细胞的早期凋亡增强。Parg−/− ES细胞主要经历半胱天冬酶依赖性凋亡。然后在p53缺陷细胞系MIAPaCa 2细胞（一种人胰腺癌细胞系）中敲低PARG。通过PARG敲低使MIAPaCa 2细胞对MMS敏感。在增加γ-H2 AX水平和S期阻滞后，在MIAPaCa 2细胞中诱导了增强的坏死细胞死亡。总之，这些数据表明，DSB修复缺陷导致S期阻滞，但p53状态是不重要的敏感性烷基化DNA损伤的PARG功能障碍，而细胞死亡途径是依赖于细胞类型。该研究表明，PARG的功能抑制可用于使至少特定癌细胞对烷化剂敏感。
Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme responsible for the degradation of poly(ADP-ribose). PARG dysfunction sensitizes cells to alkylating agents and induces cell death; however, the details of this effect have not been fully elucidated. Here, we investigated the mechanism by which PARG deficiency leads to cell death in different cell types using methylmethanesulfonate (MMS), an alkylating agent, and Parg−/− mouse ES cells and human cancer cell lines. Parg−/− mouse ES cells showed increased levels of γ-H2AX, a marker of DNA double strand breaks (DSBs), accumulation of poly(ADP-ribose), p53 network activation, and S-phase arrest. Early apoptosis was enhanced in Parg−/− mouse ES cells. Parg−/− ES cells predominantly underwent caspase-dependent apoptosis. PARG was then knocked down in a p53-defective cell line, MIAPaCa2 cells, a human pancreatic cancer cell line. MIAPaCa2 cells were sensitized to MMS by PARG knockdown. Enhanced necrotic cell death was induced in MIAPaCa2 cells after augmenting γ-H2AX levels and S-phase arrest. Taken together, these data suggest that DSB repair defect causing S-phase arrest, but p53 status was not important for sensitization to alkylation DNA damage by PARG dysfunction, whereas the cell death pathway is dependent on the cell type. This study demonstrates that functional inhibition of PARG may be useful for sensitizing at least particular cancer cells to alkylating agents.
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影响因子：
4
作者：
Ame, Jean-Christophe;Fouquerel, Elise;Schreiber, Valerie
通讯作者：
Schreiber, Valerie
影响因子：
5.3
作者：
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通讯作者：
Caldecott, Keith W.
影响因子：
4.8
作者：
Oka, S;Kato, J;Moss, J
通讯作者：
Moss, J
DOI：
10.1073/pnas.0606526103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Andrabi, Shaida A.;Kim, No Soo;Dawson, Ted M.
通讯作者：
Dawson, Ted M.
DOI：
10.1073/pnas.2237114100
发表时间：
2004-01-06
影响因子：
11.1
作者：
Hanai, S;Kanai, M;Miwa, M
通讯作者：
Miwa, M