DNA damage signaling guards against perturbation of cyclin D1 expression triggered by low-dose long-term fractionated radiation.
DNA damage signaling guards against perturbation of cyclin D1 expression triggered by low-dose long-term fractionated radiation.
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DOI：
10.1038/oncsis.2014.48
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发表时间：
2014-12-08
期刊：
影响因子：
6.2
通讯作者：
Kunugita, N.
中科院分区：
文献类型：
--
作者：
Shimura, T.;Kobayashi, J.;Komatsu, K.;Kunugita, N.
Cyclin D1的表达在细胞周期进程中受到精确控制。然而，在正常人成纤维细胞中，反复暴露于低剂量分次辐射（FR）可通过组成性激活AKT存活信号来消除细胞周期依赖性cyclin D1降解。由此导致的核周期蛋白D1异常积累诱导DNA复制缺陷和DNA双链断裂，并与诱导低剂量辐照细胞的基因组不稳定性有关。在这里，我们研究了DNA损伤信号在细胞周期对cyclin D1表达的干扰控制中的作用。在ATM缺陷细胞（AT5BIVA）中，低剂量FR （0.01 Gy或0.05 Gy /分数）在7天内诱导了核周期蛋白D1的积累，但在携带人类ATM cDNA的AT5BIVA细胞中则晚些时候出现。因此，ATM可在低剂量FR后早期时间点阻止核cyclin D1异常积累。我们进一步证明，ATM介导的蛋白磷酸酶2A活性下调可在长期FR后激活AKT/cyclin D1通路。而ATM-和NBS1缺陷细胞（GM7166）在长期低剂量FR后不能诱导Rad51灶。FR 21天后，NBS1-和ATM缺陷细胞的核周期蛋白d1阳性细胞减少，凋亡细胞增加。同样，KU55933抑制ATM通过诱导低剂量FR的ATM补充细胞凋亡来消除核周期蛋白D1的积累。总之，我们在这里证明ATM参与控制低剂量FR后的周期蛋白D1水平。DNA损伤信号通过抑制细胞周期蛋白D1表达扰动引起的细胞死亡来减轻低剂量长期FR的有害影响。
Cyclin D1 expression is precisely controlled during cell-cycle progression. However, repeated exposure to low-dose fractionated radiation (FR) abrogates cell cycle-dependent cyclin D1 degradation by constitutive activation of AKT survival signaling in normal human fibroblasts. The resulting abnormal nuclear cyclin D1 accumulation induces defects in DNA replication and resulting DNA double-strand breaks, and is associated with induction of genomic instability in low-dose irradiated cells. Here, we investigated the role of DNA damage signaling against such perturbed cell-cycle control of cyclin D1 expression. Nuclear cyclin D1 accumulation was induced within 7 days after low-dose FR (0.01 Gy or 0.05 Gy per fraction) in ATM-deficient cells (AT5BIVA), but appeared later in AT5BIVA cells harboring human ATM cDNA. Thus, ATM prevents abnormal nuclear cyclin D1 accumulation at early time points after low-dose FR. We further demonstrated that ATM-mediated downregulation of protein phosphatase 2A activity caused activation of the AKT/cyclin D1 pathway after long-term FR. Perturbation of cyclin D1 expression induced Rad51 foci that indicate homologous recombination repair (HRR) in control cells, while ATM- and NBS1-deficient cells (GM7166) failed to induce Rad51 foci after long-term low-dose FR. After 21 days of FR, NBS1- and ATM-deficient cells showed a decrease in nuclear cyclin D1-positive cells, and an increase in apoptotic cells. Similarly, inhibition of ATM with KU55933 abrogated nuclear cyclin D1 accumulation by induction of apoptosis in ATM-complemented cells exposed to low-dose FR. In conclusion, we here demonstrate that ATM is involved in controlling cyclin D1 levels after low-dose FR. DNA damage signaling mitigates the harmful effects of low-dose long-term FR by suppression of cell death induced by perturbation of cyclin D1 expression.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
11.2
作者：
Li Z;Jiao X;Wang C;Shirley LA;Elsaleh H;Dahl O;Wang M;Soutoglou E;Knudsen ES;Pestell RG
通讯作者：
Pestell RG
影响因子：
12.4
作者：
Liu, W;Akhand, AA;Nakashima, I
通讯作者：
Nakashima, I
影响因子：
8
作者：
Shimura, T.;Toyoshima, M.;Niwa, O.
通讯作者：
Niwa, O.