Sequential binding of UV DNA damage binding factor and degradation of the p48 subunit as early events after UV irradiation
Sequential binding of UV DNA damage binding factor and degradation of the p48 subunit as early events after UV irradiation
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DOI：
10.1093/nar/30.11.2588
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发表时间：
2002-06-01
影响因子：
14.9
通讯作者：
Levine, AS
中科院分区：
文献类型：
--
作者：
Rapic-Otrin, V;McLenigan, MP;Levine, AS
紫外线损伤的DNA结合蛋白复合物（UV-DDB）参与哺乳动物细胞的全基因组核苷酸切除修复（NER）。该复合物由p127和p48的异二聚体组成。UV-DDB在可遗传的皮肤癌易感性疾病着色性干皮病的一个互补组（XP-E）中有缺陷。在灵长类动物细胞的UV照射后，UV-DDB与染色质紧密结合，伴随着可提取的结合活性的丧失。我们在这里报告的早期事件后，紫外线，但不是电离辐射是短暂的剂量依赖性降解的小亚基，p48。用蛋白酶体抑制剂NIP-L3 VS处理人类细胞可以阻断这种紫外线诱导的p48降解。在UV-DDB结合受损的XP-E细胞系中，p48对降解具有抗性。UV介导的p48降解的发生独立于p53的表达和细胞对NER的熟练程度，但在稍后的时间（12小时及以后）p48水平的恢复取决于细胞修复非转录DNA的能力。此外，我们发现UV-DDB的p127亚基在体内与组蛋白乙酰转移酶p300结合。这些数据支持在NER的早期步骤中UV-DDB结合活性、p48的蛋白酶体降解和染色质重塑之间的功能联系。
The UV-damaged DNA binding protein complex (UV-DDB) is implicated in global genomic nucleotide excision repair (NER) in mammalian cells. The complex consists of a heterodimer of p127 and p48. UV-DDB is defective in one complementation group (XP-E) of the heritable, skin cancer-prone disorder xeroderma pigmentosum. Upon UV irradiation of primate cells, UV-DDB associates tightly with chromatin, concomitant with the loss of extractable binding activity. We report here that an early event after UV, but not ionizing, radiation is the transient dose-dependent degradation of the small subunit, p48. Treatment of human cells with the proteasomal inhibitor NIP-L3VS blocks this UV-induced degradation of p48. In XP-E cell lines with impaired UV-DDB binding, p48 is resistant to degradation. UV-mediated degradation of p48 occurs independently of the expression of p53 and the cell's proficiency for NER, but recovery of p48 levels at later times (12 h and thereafter) is dependent upon the capacity of the cell to repair non-transcribed DNA. In addition, we find that the p127 subunit of UV-DDB binds in vivo to p300, a histone acetyltransferase. The data support a functional connection between UV-DDB binding activity, proteasomal degradation of p48 and chromatin remodeling during early steps of NER.