The DNA repair function of CUX1 contributes to radioresistance.
The DNA repair function of CUX1 contributes to radioresistance.
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DOI：
10.18632/oncotarget.14875
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Nepveu A
中科院分区：
文献类型：
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作者：
Ramdzan ZM;Ginjala V;Pinder JB;Chung D;Donovan CM;Kaur S;Leduy L;Dellaire G;Ganesan S;Nepveu A
电离辐射会产生广泛的氧化 DNA 损伤，包括氧化碱基产物、无碱基位点、单链断裂和双链断裂。 CUX1 蛋白最近被证明可以作为辅助因子，通过其 CUT 结构域刺激 OGG1 的酶活性。在本研究中，我们研究了 CUX1 和 OGG1 在抗辐射方面的要求。电离辐射后癌细胞的存活率会因 CUX1 敲除而降低，并因 CUX1 表达升高而增加。然而，CUX1 敲低本身就足以降低许多活性氧 (ROS) 水平较高的癌细胞系的活力。因此，相对于未照射细胞的克隆形成结果表明，CUX1 敲低不会赋予具有高 ROS 的癌细胞没有或适度的放射敏感性。仅包含两个 CUT 结构域的重组蛋白足以快速招募 DNA 损伤、加速 DNA 修复并提高辐射后的存活率。与这些发现一致的是，OGG1 敲低和 OGG1 抑制剂处理细胞使癌细胞对辐射敏感。总之，这些结果验证了 CUX1，更具体地说，CUT 结构域作为治疗靶点。
Ionizing radiation generates a broad spectrum of oxidative DNA lesions, including oxidized base products, abasic sites, single-strand breaks and double-strand breaks. The CUX1 protein was recently shown to function as an auxiliary factor that stimulates enzymatic activities of OGG1 through its CUT domains. In the present study, we investigated the requirement for CUX1 and OGG1 in the resistance to radiation. Cancer cell survival following ionizing radiation is reduced by CUX1 knockdown and increased by higher CUX1 expression. However, CUX1 knockdown is sufficient by itself to reduce viability in many cancer cell lines that exhibit high levels of reactive oxygen species (ROS). Consequently, clonogenic results expressed relative to that of non-irradiated cells indicate that CUX1 knockdown confers no or modest radiosensitivity to cancer cells with high ROS. A recombinant protein containing only two CUT domains is sufficient for rapid recruitment to DNA damage, acceleration of DNA repair and increased survival following radiation. In agreement with these findings, OGG1 knockdown and treatment of cells with OGG1 inhibitors sensitize cancer cells to radiation. Together, these results validate CUX1 and more specifically the CUT domains as therapeutic targets.