Germline stem cell gene PIWIL2 mediates DNA repair through relaxation of chromatin.
Germline stem cell gene PIWIL2 mediates DNA repair through relaxation of chromatin.
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生殖干细胞基因 PIWIL2 通过染色质松弛介导 DNA 修复。
DOI：
10.1371/journal.pone.0027154
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Gao JX
中科院分区：
文献类型：
--
作者：
Yin DT;Wang Q;Chen L;Liu MY;Han C;Yan Q;Shen R;He G;Duan W;Li JJ;Wani A;Gao JX
DNA损伤反应(DDR)是细胞对遗传毒物引发的肿瘤发生的一种固有屏障。然而，尽管进行了广泛的调查，但引发解甲返乡的机制并不完全清楚。最近，我们报道了生殖系干细胞基因PIWIL2的异位表达与肿瘤干细胞的发展有关，尽管其潜在的机制在很大程度上尚不清楚。在这里，我们证明了PIWIL2是修复由各种类型的遗传毒物引起的DNA损伤所必需的。在紫外线照射下，正常人成纤维细胞中沉默的PIWIL2基因在紫外线照射后被瞬时激活。这种激活与DNA修复有关，因为PIWIL2缺陷的小鼠胚胎成纤维细胞(Mili-/-MEF)在紫外线处理后的环丁烷嘧啶二聚体(CPD)修复方面存在缺陷。因此，紫外线处理的Mili-/-MEF更容易发生凋亡，其特征是与DNA损伤相关的凋亡蛋白水平增加，如活性caspase-3、裂解多聚(ADP-核糖)聚合酶(PARP)和Bik。MILI-/-MEF的DNA修复受损与组蛋白H3乙酰化和染色质松弛的减少有关，尽管染色质松弛下游的DDR途径似乎不受PIWIL2的直接影响。此外，在用顺铂和电离辐射(IR)处理的mALI-/-MEF中，鸟嘌呤-鸟嘌呤(Pt-[GG])和双链断裂(DSB)修复也存在缺陷。结果表明，PIWIL2可通过→、组蛋白乙酰化、→染色质松弛等途径介导DNA修复。这些发现揭示了PIWIL2在DNA修复中的新作用，并表明PIWIL2可能是阻止DNA损伤介导的肿瘤发生的守门人。
DNA damage response (DDR) is an intrinsic barrier of cell to tumorigenesis initiated by genotoxic agents. However, the mechanisms underlying the DDR are not completely understood despite of extensive investigation. Recently, we have reported that ectopic expression of germline stem cell gene PIWIL2 is associated with tumor stem cell development, although the underlying mechanisms are largely unknown. Here we show that PIWIL2 is required for the repair of DNA-damage induced by various types of genotoxic agents. Upon ultraviolet (UV) irradiation, silenced PIWIL2 gene in normal human fibroblasts was transiently activated after treatment with UV light. This activation was associated with DNA repair, because Piwil2-deficienct mouse embryonic fibroblasts (mili-/- MEFs) were defective in cyclobutane pyrimidine dimers (CPD) repair after UV treatment. As a result, the UV-treated mili-/- MEFs were more susceptible to apoptosis, as characterized by increased levels of DNA damage-associated apoptotic proteins, such as active caspase-3, cleaved Poly (ADP-ribose) polymerase (PARP) and Bik. The impaired DNA repair in the mili-/- MEFs was associated with the reductions of histone H3 acetylation and chromatin relaxation, although the DDR pathway downstream chromatin relaxation appeared not to be directly affected by Piwil2. Moreover, guanine–guanine (Pt-[GG]) and double strand break (DSB) repair were also defective in the mili-/- MEFs treated by genotoxic chemicals Cisplatin and ionizing radiation (IR), respectively. The results indicate that Piwil2 can mediate DNA repair through an axis of Piwil2 → histone acetylation → chromatin relaxation upstream DDR pathways. The findings reveal a new role for Piwil2 in DNA repair and suggest that Piwil2 may act as a gatekeeper against DNA damage-mediated tumorigenesis.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
DOI：
10.1073/pnas.0307337101
发表时间：
2004-02-24
影响因子：
11.1
作者：
Hur, JY;Chesnes, J;Shioda, T
通讯作者：
Shioda, T
影响因子：
5.3
作者：
Gao JX
通讯作者：
Gao JX
影响因子：
3.4
作者：
DEALMODOVAR, JMR;BUSH, C;MCMILLAN, TJ
通讯作者：
MCMILLAN, TJ
影响因子：
10.5
作者：
Grivna, Shane T.;Beyret, Ergin;Lin, Haifan
通讯作者：
Lin, Haifan