Radiation-induced mitotic catastrophe in PARG-deficient cells
Radiation-induced mitotic catastrophe in PARG-deficient cells
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DOI：
10.1242/jcs.039115
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发表时间：
2009-06-15
影响因子：
4
通讯作者：
Schreiber, Valerie
中科院分区：
文献类型：
--
作者：
Ame, Jean-Christophe;Fouquerel, Elise;Schreiber, Valerie
聚（ADP-核糖基）化是蛋白质的翻译后修饰，其参与调节染色质结构、DNA代谢、细胞分裂和细胞死亡。聚ADP核糖糖水解酶（Poly（ADP-ribose）glycohydrolase，PARG）通过水解聚ADP核糖（Poly（ADP-ribose），PAR）在DNA损伤后的生死平衡调控中发挥重要作用。PARG功能的理解受到了由单个基因编码的许多PARG异构体的存在的阻碍，并显示出各种亚细胞定位。为了深入了解PARG在辐射响应中的功能，我们组成性地和稳定地敲低HeLa细胞中PARG同种型的表达。PARG耗竭导致PAR积累对未受损细胞无害，实际上是相当有益的，因为它保护细胞免受自发性单链断裂和端粒异常。相比之下，PARG缺陷细胞表现出增加的放射敏感性，由单和双链断裂的修复缺陷和有丝分裂纺锤体检查点缺陷引起，导致有丝分裂进程的改变。辐射PARG缺陷细胞显示中心体扩增，导致有丝分裂额外的纺锤体极，并积累异常的有丝分裂数字，诱导多倍体或细胞死亡的有丝分裂灾难。我们的研究结果表明，PARG可能是一个新的潜在的放射治疗靶点。
Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in the regulation of chromatin structure, DNA metabolism, cell division and cell death. Through the hydrolysis of poly(ADP-ribose) (PAR), Poly(ADP-ribose) glycohydrolase (PARG) has a crucial role in the control of life-and-death balance following DNA insult. Comprehension of PARG function has been hindered by the existence of many PARG isoforms encoded by a single gene and displaying various subcellular localizations. To gain insight into the function of PARG in response to irradiation, we constitutively and stably knocked down expression of PARG isoforms in HeLa cells. PARG depletion leading to PAR accumulation was not deleterious to undamaged cells and was in fact rather beneficial, because it protected cells from spontaneous single-strand breaks and telomeric abnormalities. By contrast, PARG-deficient cells showed increased radiosensitivity, caused by defects in the repair of single- and double-strand breaks and in mitotic spindle checkpoint, leading to alteration of progression of mitosis. Irradiated PARG-deficient cells displayed centrosome amplification leading to mitotic supernumerary spindle poles, and accumulated aberrant mitotic figures, which induced either polyploidy or cell death by mitotic catastrophe. Our results suggest that PARG could be a novel potential therapeutic target for radiotherapy.