Beclin 1 and UVRAG confer protection from radiation-induced DNA damage and maintain centrosome stability in colorectal cancer cells.
Beclin 1 and UVRAG confer protection from radiation-induced DNA damage and maintain centrosome stability in colorectal cancer cells.
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DOI：
10.1371/journal.pone.0100819
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sinicrope FA
中科院分区：
文献类型：
--
作者：
Park JM;Tougeron D;Huang S;Okamoto K;Sinicrope FA
Beclin 1与抗紫外线相关基因（UVRAG）相互作用形成核心复合物，诱导自噬。虽然具有缺陷性自噬的细胞易于发生基因组不稳定性，从而导致肿瘤发生，但目前尚不清楚Beclin 1或UVRAG是否可以调节已建立的肿瘤细胞对癌症治疗的DNA损伤/修复反应。我们发现Beclin 1或UVRAG的siRNA敲低可以增加辐射诱导的DNA双链断裂（DSB），如pATM和γ H2 Ax所示，并促进结直肠癌细胞死亡。此外，与对照siRNA相比，Beclin 1、UVRAG或ATG 5的敲低增加了具有表达53 BP 1（非同源末端连接而非RAD 51（同源重组）的标志物）的核灶的辐照细胞的百分比。Beclin 1 siRNA显示减弱UVRAG表达。与异位野生型UVRAG的细胞相比，具有UVRAG缺失突变体的Beclin 1结合缺陷的细胞显示出增加的辐射诱导的DSB和细胞死亡。与对照siRNA相比，Beclin 1或UVRAG而非ATG 5的敲低导致辐照细胞中中心体数目（γ-微管蛋白染色）的显著增加。综上所述，这些数据表明，Beclin 1和UVRAG赋予针对辐射诱导的DNA DSB的保护作用，并且可以在已建立的肿瘤细胞中维持中心体稳定性。
Beclin 1 interacts with UV-irradiation-resistance-associated gene (UVRAG) to form core complexes that induce autophagy. While cells with defective autophagy are prone to genomic instability that contributes to tumorigenesis, it is unknown whether Beclin1 or UVRAG can regulate the DNA damage/repair response to cancer treatment in established tumor cells. We found that siRNA knockdown of Beclin 1 or UVRAG can increase radiation-induced DNA double strand breaks (DSBs), shown by pATM and γH2Ax, and promote colorectal cancer cell death. Furthermore, knockdown of Beclin 1, UVRAG or ATG5 increased the percentage of irradiated cells with nuclear foci expressing 53BP1, a marker of nonhomologous end joining but not RAD51 (homologous recombination), compared to control siRNA. Beclin 1 siRNA was shown to attenuate UVRAG expression. Cells with a UVRAG deletion mutant defective in Beclin 1 binding showed increased radiation-induced DSBs and cell death compared to cells with ectopic wild-type UVRAG. Knockdown of Beclin 1 or UVRAG, but not ATG5, resulted in a significant increase in centrosome number (γ-tubulin staining) in irradiated cells compared to control siRNA. Taken together, these data indicate that Beclin 1 and UVRAG confer protection against radiation-induced DNA DSBs and may maintain centrosome stability in established tumor cells.
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DOI：
10.4161/cc.7.18.6679
发表时间：
2008-09-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Mao Z;Bozzella M;Seluanov A;Gorbunova V
通讯作者：
Gorbunova V
影响因子：
10.5
作者：
Mathew, Robin;Kongara, Sameera;White, Eileen
通讯作者：
White, Eileen
影响因子：
7.7
作者：
Fremont, Stephane;Gerard, Annabelle;Berlioz-Torrent, Clarisse
通讯作者：
Berlioz-Torrent, Clarisse
影响因子：
16
作者：
Bothmer A;Robbiani DF;Di Virgilio M;Bunting SF;Klein IA;Feldhahn N;Barlow J;Chen HT;Bosque D;Callen E;Nussenzweig A;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
9.2
作者：
Paull, TT;Rogakou, EP;Bonner, WM
通讯作者：
Bonner, WM