CUL4A abrogation augments DNA damage response and protection against skin carcinogenesis.
CUL4A abrogation augments DNA damage response and protection against skin carcinogenesis.
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DOI：
10.1016/j.molcel.2009.04.020
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发表时间：
2009-05-14
期刊：
影响因子：
16
通讯作者：
Zhou, Pengbo
中科院分区：
文献类型：
--
作者：
Liu, Liren;Lee, Sharrell;Zhang, Jianxuan;Peters, Sara B.;Hannah, Jeffrey;Zhang, Yue;Yin, Yan;Koff, Andrew;Ima, Liang;Zhou, Pengbo
很明显，细胞修复DNA损伤的能力是饱和的，要么是受到酶活性的限制，要么是实现其功能的时间分配，或者两者兼而有之。然而，关于建立这样一个门槛的机制，人们知之甚少。在这里，我们证明了CUL4A泛素连接酶通过选择性地降解DDB2DNA损伤传感器和XPCDNA损伤传感器以及p21/CIP1/WAF1检查点效应蛋白来协调核苷酸切除修复(NER)和DNA损伤响应G1/S检查点的协同作用，从而限制细胞的修复能力。我们建立了cul4a条件性基因敲除小鼠，并观察到皮肤特异的cul4a消融显著增加了对紫外线诱导的皮肤癌的抵抗力。我们的发现揭示了野生型细胞没有以其全部的DNA修复潜力运作，强调了CUL4A在建立细胞DNA修复阈值方面的关键作用，并强调了通过药物抑制CUL4A来增强细胞修复熟练程度的可能性。
It is intuitively obvious that the ability of a cell to repair DNA damage is saturable, either by limitation of enzymatic activities, the time allotted to achieve their function, or both. However, very little is known regarding the mechanisms that establish such a threshold. Here we demonstrated that the CUL4A ubiquitin ligase restricts the cellular repair capacity by orchestrating the concerted actions of nucleotide excision repair (NER) and the DNA damage-responsive G1/S checkpoint through selective degradation of the DDB2 and XPC DNA damage sensors and the p21/CIP1/WAF1 checkpoint effector. We generated Cul4a conditional knockout mice and observed that skin-specific Cul4a ablation dramatically increased resistance to UV-induced skin carcinogenesis. Our findings reveal that wild-type cells do not operate at their full DNA repair potential, underscore the critical role of CUL4A in establishing the cellular DNA repair threshold, and highlight the potential augmentation of cellular repair proficiency by pharmacological CUL4A inhibition.
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影响因子：
10.5
作者：
LaBaer, J;Garrett, MD;Harlow, E
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