Liu Y, Kulesz-Martin M
Department of Dermatology and Oregon Cancer Center, Oregon Health Sciences University, Portland, OR 97201, USA.
Carcinogenesis. 2001 Jun;22(6):851-60. doi: 10.1093/carcin/22.6.851.
Our environment contains physical, chemical and pathological agents that challenge the integrity of our DNA. In addition to DNA repair, higher multicellular organisms have evolved multiple pathways of response to damage including programmed cell death-apoptosis. The p53 protein appears to sense multiple types of DNA damage and coordinate with multiple options for cellular response. The p53 protein activities depend upon its DNA binding. Specific p53 protein post-translational modifications are required for efficient sequence-specific binding and transcriptional activities. Non-sequence-specific DNA binding may involve a wide spectrum of p53 proteins and predominate as DNA damage is more severe or p53 protein is more highly induced. p53 protein is not strictly required for DNA damage sensing and repair. Rather, p53 protein may govern an apoptosis checkpoint through competition with DNA repair proteins for non-sequence-specific binding to exposed single-stranded regions in the DNA duplex. This model provides a framework for testing mechanisms of p53-mediated apoptosis dependent upon the p53 protein modification state, the level of p53 protein accumulation, the level of DNA damage and the capacity of the damaged cell to repair.
我们的环境中存在着挑战我们DNA完整性的物理、化学和病理因子。除了DNA修复外，高等多细胞生物还进化出了多种应对损伤的途径，包括程序性细胞死亡——凋亡。p53蛋白似乎能感知多种类型的DNA损伤，并协调细胞反应的多种选择。p53蛋白的活性取决于其与DNA的结合。高效的序列特异性结合和转录活性需要特定的p53蛋白翻译后修饰。非序列特异性DNA结合可能涉及多种p53蛋白，并且在DNA损伤更严重或p53蛋白诱导程度更高时占主导地位。DNA损伤的感知和修复并不严格需要p53蛋白。相反，p53蛋白可能通过与DNA修复蛋白竞争，以非序列特异性方式结合DNA双链中暴露的单链区域，从而控制凋亡检查点。该模型为测试依赖于p53蛋白修饰状态、p53蛋白积累水平、DNA损伤水平以及受损细胞修复能力的p53介导的凋亡机制提供了一个框架。
