Deletion of the nuclear isoform of poly(ADP-ribose) glycohydrolase (PARG) reveals its function in DNA repair, genomic stability and tumorigenesis
Deletion of the nuclear isoform of poly(ADP-ribose) glycohydrolase (PARG) reveals its function in DNA repair, genomic stability and tumorigenesis
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DOI：
10.1093/carcin/bgq205
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发表时间：
2010-12-01
期刊：
影响因子：
4.7
通讯作者：
Wang, Zhao-Qi
中科院分区：
文献类型：
--
作者：
Min, WooKee;Cortes, Ulrich;Wang, Zhao-Qi
聚(ADP-核糖)代谢主要由聚(ADP-核糖)聚合酶(PARP)1和聚(ADP-核糖)糖水解酶(PARG)介导，调节多种细胞过程以响应基因毒性应激。PARP1已被证明在多种细胞过程中起重要作用，包括DNA修复、染色体稳定性、染色质功能、细胞凋亡和转录调控。然而，PARP1的S聚合物合成活性或聚合物动态平衡是否对这些功能负责仍是很大程度上未知的。鉴于多个PARP和独特的PARG在聚(ADP-核糖基)的动态平衡中的协同作用，PARG被假设在这些过程中发挥作用。然而，小鼠胚胎中PARG零突变的致死性表型阻碍了对PARG生物学功能的进一步研究。在这里，我们发现，携带PARG亚型突变的小鼠胚胎成纤维细胞，即缺乏核110kD亚型(PARG(110)(-/-))的小鼠胚胎成纤维细胞，在修复由各种遗传毒性物质引起的DNA损伤方面存在缺陷。PARG(110)(-/-)细胞表现出基因组不稳定，其特征是高频率的姐妹染色单体交换、微核形成和染色体异常。此外，突变细胞含有多余的中心体，这是基因组不稳定的另一个标志，这与复制毒药后S期细胞的积累有关。有趣的是，PARG(110)(-/-)细胞对羟基脲的反应积累了更多的RAD51焦点，表明复制叉状损伤的修复存在缺陷。最后，PARG(110)(-/-)小鼠易患二乙基亚硝胺诱导的肝细胞癌。这些数据表明，聚(ADP-核糖基)的动态平衡对于有效地修复受损的复制叉和稳定基因组，从而防止癌症的发生是重要的。
Poly(ADP-ribose) metabolism, mediated mainly by poly(ADP-ribose) polymerase (PARP) 1 and poly(ADP-ribose) glycohydrolase (PARG), regulates various cellular processes in response to genotoxic stress. PARP1 has been shown to be important in multiple cellular processes, including DNA repair, chromosomal stability, chromatin function, apoptosis and transcriptional regulation. However, whether PARP1's polymer synthesizing activity or polymer homeostasis is responsible for these functions remains largely unknown. Given a concerted action of multiple PARPs and unique PARG in the homeostasis of poly(ADP-ribosyl)ation, PARG is hypothesized to function in these processes. The lethal phenotype of the PARG null mutation in mouse embryos, however, hampers further investigation on biological function of PARG. Here, we show that mouse embryonic fibroblasts carrying a hypomorphic mutation of PARG, i.e. lacking the nuclear 110 kD isoform (PARG(110)(-/-)), have defects in the repair of DNA damage caused by various genotoxic agents. PARG(110)(-/-) cells exhibit genomic instability, characterized by a high frequency of sister chromatid exchange, micronuclei formation and chromosomal aberrations. Moreover, mutant cells contain supernumerary centrosomes, another hallmark of genomic instability, which correlates with an accumulation of S-phase cells after replication poison. Intriguingly, PARG(110)(-/-) cells accumulate more Rad51 foci in response to hydroxyurea, indicative of a defective repair of replication fork damage. Finally, PARG(110)(-/-) mice are susceptible to diethylnitrosamine-induced hepatocellular carcinoma. These data demonstrate that the homeostasis of poly(ADP-ribosyl)ation is important for an efficient DNA repair of damaged replication forks and for stabilizing the genome, thereby preventing carcinogenesis.