辐射诱导LNC CRYBG3靶向Bub3-Cdc20复合体导致纺锤体组装检验点逃逸的机制研究

辐射诱导的基因组不稳定，尤其以整条染色体得失为特征的非整倍体形成，是肿瘤发生的关键早期事件，也是肿瘤复发的重要原因。目前国内外对辐射诱导非整倍体的调控开关尚不明确。申请者发现辐射诱导LNC CRYBG3，其高拷贝过表达引起细胞凋亡，低拷贝过表达细胞增殖反而显著加快；LNC CRYBG3抑制G-actin的聚合且Bub3与之解绑，因此提出其靶向纺锤体组装检验点，调控辐射诱导非整倍体发生这一假说。.拟研究：.1 辐射及LNC CRYBG3对非整倍体发生的调控作用。.2 LNC CRYBG3与Actin、Bub3（Bub R1、Cdc20、APC/C复合体）、DNA-PKcs的定位和相互作用关系。.3 LNC CRYBG3对辐射致肺上皮细胞转化的影响。.探讨LNC CRYBG3对Actin-Bub3-Cdc20这一信号通路的调控机制，对于揭示辐射导致肺癌发生的机制和肺癌的靶向治疗具有重要意义。

Radiation-induced genomic instability, especially the formation of aneuploidy characterized by the gain and loss of the whole chromosome, is a key early event in tumorigenesis and an important cause of recurrence after treatment. So far, the regulatory mechanism of radiation-induced chromosome instability is not clear. We found that LNC CRYBG3 could be induced by radiation. High-copy overexpression of LNC CRYBG3 induced apoptosis, while low-copy overexpression promoted cell proliferation. LNC CRYBG3 significantly inhibit polymerization of G-actin leading cells arrested to M phase. Co-IP experiment showed that Bub3 and Actin were unbounded after low-copy overexpression of LNC CRYBG3. Therefore, we hypothesis that LNC CRYBG3 targeting spindle assembly checkpoint pathway to regulate radiation induced aneuploidy..We intend to investigate:.1..The relationship between aneuploidy and LNC CRYBG3..2..Subcellular localization and interaction between Actin, Bub3 (Bub R1, Cdc20, APC/C complex), DNA-PKCS after LNC CRYBG3 treatment.3..The effect of LNC CRYBG3 on the tumorigenicity in pulmonary epithelial cells..The successful accomplishment of this project is supposed to be of great great significance to reveal the mechanism of radiation-induced tumorigenesis and targeted therapy of tumors.