Keeping mammalian mutation load in check - Regulation of the activity of error-prone DNA polymerases by p53 and p21
Keeping mammalian mutation load in check - Regulation of the activity of error-prone DNA polymerases by p53 and p21
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DOI：
10.4161/cc.5.17.3193
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发表时间：
2006-09-01
期刊：
影响因子：
4.3
通讯作者：
Livneh, Zvi
中科院分区：
文献类型：
--
作者：
Livneh, Zvi
为了克服阻碍复制的DNA损伤，细胞使用翻译DNA合成（TLS）聚合酶，这是一组低保真DNA聚合酶，具有绕过大范围DNA损伤的能力。由于其固有的诱变性质，这个TLS过程也被称为易出错修复。我们最近发现肿瘤抑制因子p53和细胞周期抑制因子p21是TLS的全局调控因子。当这些蛋白质缺失或失去功能时，TLS就会失去控制：其范围增加到非常高的水平，其保真度降低，从而导致突变负荷的总体增加。这可能是由于同源的特异性聚合酶在绕过特定DNA损伤时失去了选择性，因此，尽管付出了增加突变的代价，但病变的旁路仍然最大限度地进行。p53和p21蛋白也是有效的紫外光诱导的PCNA单泛素化所必需的，这与一个模型是一致的，即PCNA的这种修饰是必要的，但对于TLS的正常活性是不够的。这一调控表明，TLS在哺乳动物中进化为一种平衡生存收益与可容忍的突变成本的系统，破坏这种平衡会导致潜在的有害突变增加，这可能在致癌过程中发挥作用。
To overcome DNA lesions that block replication the cell employs translesion DNA synthesis (TLS) polymerases, a group of low fidelity DNA polymerases that have the capacity to bypass a wide range of DNA lesions. This TLS process is also termed error-prone repair, due to its inherent mutagenic nature. We have recently shown that the tumor suppressor p53 and the cell cycle inhibitor p21 are global regulators of TLS. When these proteins are missing or nonfunctional, TLS gets out of control: its extent increases to very high levels, and its fidelity decreases, causing an overall increase in mutation load. This may be explained by the loss of selectivity in the bypass of specific DNA lesions by their cognate specialized polymerases, such that lesion bypass continues to a maximum, regardless of the price paid in increased mutations. The p53 and p21 proteins are also required for efficient UV light-induced monoubiquitination of PCNA, which is consistent with a model in which this modification of PCNA is necessary but not sufficient for the normal activity of TLS. This regulation suggests that TLS evolved in mammals as a system that balances gain in survival with a tolerable mutational cost, and that disturbing this balance causes a potentially harmful increase in mutations, which might play a role in carcinogenesis.