c-Myc Suppression of DNA Double-strand Break Repair
c-Myc Suppression of DNA Double-strand Break Repair
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DOI：
10.1593/neo.121258
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发表时间：
2012-12-01
期刊：
影响因子：
4.8
通讯作者：
Deng, Xingming
中科院分区：
文献类型：
--
作者：
Li, Zhaozhong;Owonikoko, Taofeek K.;Deng, Xingming
C-Myc是一种转录因子，在细胞生长、增殖和凋亡中起中心调节作用。C-Myc的过表达还会增加DNA双链断裂(DSB)、遗传不稳定性和肿瘤发生。然而，其中涉及的机制(S)仍然难以捉摸。在这里，我们发现伽马射线电离辐射诱导的DSB促进c-Myc形成焦点并与伽马-H_2AX共定位。利用Tet-Off/Tet-On诱导系统在HO15.19 c-Myc缺失细胞中条件性表达c-Myc，导致Ku DNA结合下调，DNA依赖蛋白激酶催化亚单位(DNA-PKcs)和DNA末端连接活性受到抑制，导致DSB修复抑制，染色体和染色单体断裂增加。在V(D)J重组过程中，c-Myc的表达减少了信号连接和编码连接，保真度降低。在机制上，c-Myc通过其Myc box II(MBII)结构域与Ku70蛋白直接相互作用。从c-Myc上去除MBII结构域会消除其对Ku DNA结合、DNA-PKcs和DNA末端连接活性的抑制作用，从而导致c-Myc失去阻止DSB修复和V(D)J重组的能力。有趣的是，c-Myc在体外和体内都直接破坏Ku/DNA-PKcs复合体。因此，c-Myc对DSB修复和V(D)J重组的抑制可能是通过抑制非同源末端连接途径发生的，这为深入了解c-Myc通过促进基因组不稳定性而在肿瘤发生发展中的作用机制提供了新的思路。肿瘤(2012)14,1190-1202
c-Myc is a transcriptional factor that functions as a central regulator of cell growth, proliferation, and apoptosis. Overexpression of c-Myc also enhances DNA double-strand breaks (DSBs), genetic instability, and tumorigenesis. However, the mechanism(s) involved remains elusive. Here, we discovered that gamma-ray ionizing radiation-induced DSBs promote c-Myc to form foci and to co-localize with gamma-H2AX. Conditional expression of c-Myc in HO15.19 c-Myc null cells using the Tet-Off/Tet-On inducible system results in down-regulation of Ku DNA binding and suppressed activities of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and DNA end-joining, leading to inhibition of DSB repair and enhanced chromosomal and chromatid breaks. Expression of c-Myc reduces both signal and coding joins with decreased fidelity during V(D)J recombination. Mechanistically, c-Myc directly interacts with Ku70 protein through its Myc box II (MBII) domain. Removal of the MBII domain from c-Myc abrogates its inhibitory effects on Ku DNA binding, DNA-PKcs, and DNA end-joining activities, which results in loss of c-Myc's ability to block DSB repair and V(D) J recombination. Interestingly, c-Myc directly disrupts the Ku/DNA-PKcs complex in vitro and in vivo. Thus, c-Myc suppression of DSB repair and V(D) J recombination may occur through inhibition of the nonhomologous end-joining pathway, which provides insight into the mechanism of c-Myc in the development of tumors through promotion of genomic instability. Neoplasia (2012) 14, 1190-1202