Wani M A, Zhu Q Z, El-Mahdy M, Wani A A
Department of Radiology, Ohio State University, Columbus 43210, USA.
Carcinogenesis. 1999 May;20(5):765-72. doi: 10.1093/carcin/20.5.765.
A network of interacting cellular components is known to mediate the regulatory role of tumor suppressor protein p53 in genomic stability. DNA repair machinery is considered to be one of these vital cellular components. To investigate the modulatory function of p53 on the repair of DNA damage and related effects, we have studied the responses of human p53-wild-type (p53-WT), p53-mutant (p53-Mut) and p53-nullizygous (p53-Null) cells following exposure to UV irradiation. Absence of wild-type p53 function coincided with an enhanced sensitivity to UV, as well as induction of apoptosis. However, the lack of wild-type p53 expression did not affect the response of its signal transducer protein, p21. Repair analysis of specific genomic sequences, at a single nucleotide resolution, revealed that the removal of cyclobutane pyrimidine dimers in a non-transcribed strand was significantly slower in p53-Mut and p53-Null cell lines compared with the normal p53-WT cells. However, the repair of the transcribed strand was comparable in the three cell lines. Thus, p53 is required for the efficient nucleotide excision repair (NER) of the global genomic DNA, but not for the transcription-coupled repair of the essential genes. The decreased global NER, due to the lost p53 function, seems to be responsible for the conjoined cytotoxicity and apoptosis of human cells subjected to DNA stress damage.
已知相互作用的细胞成分网络介导肿瘤抑制蛋白p53在基因组稳定性中的调节作用。DNA修复机制被认为是这些重要的细胞成分之一。为了研究p53对DNA损伤修复的调节功能及相关影响，我们研究了人p53野生型（p53-WT）、p53突变型（p53-Mut）和p53纯合缺失型（p53-Null）细胞在紫外线照射后的反应。野生型p53功能的缺失与对紫外线的敏感性增强以及细胞凋亡的诱导同时发生。然而，野生型p53表达的缺失并不影响其信号转导蛋白p21的反应。在单核苷酸分辨率下对特定基因组序列的修复分析表明，与正常的p53-WT细胞相比，p53-Mut和p53-Null细胞系中非转录链中环丁烷嘧啶二聚体的去除明显更慢。然而，转录链的修复在这三种细胞系中是相当的。因此，p53是全球基因组DNA有效核苷酸切除修复（NER）所必需的，但不是必需基因转录偶联修复所必需的。由于p53功能丧失导致的全球NER降低，似乎是遭受DNA应激损伤的人类细胞联合细胞毒性和凋亡的原因。
