The retinoblastoma tumor suppressor protein is required for efficient processing and repair of trapped topoisomerase II-DNA-cleavable complexes.
The retinoblastoma tumor suppressor protein is required for efficient processing and repair of trapped topoisomerase II-DNA-cleavable complexes.
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视网膜母细胞瘤肿瘤抑制蛋白是有效加工和修复被捕获的拓扑异构酶 II-DNA 可裂解复合物所必需的。
DOI：
10.1038/sj.onc.1208958
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发表时间：
2005
期刊：
影响因子：
8
通讯作者：
Goodrich,DavidW
中科院分区：
文献类型：
--
作者：
Xiao,Hai;Goodrich,DavidW
II 型拓扑异构酶 (TOP2) 通过共价 TOP2-DNA 中间体引入短暂的双链 DNA 断裂。依托泊苷等抗癌药物通过捕获共价 TOP2-DNA 可裂解复合物来杀死细胞。影响可裂解复合物修复的途径预计将成为依托泊苷治疗反应的主要决定因素。 Rb1 是执行细胞周期检查点以应对 DNA 损伤所必需的，但缺乏在 DNA 损伤的处理和修复中直接发挥作用的证据。我们观察到，在表达 Rb1 蛋白 (pRb) 的细胞中，捕获的 TOP2 可裂解复合物的降解、DNA 链断裂的释放以及这些断裂的修复更有效地发生。缺乏 pRb 的细胞对依托泊苷诱导的细胞毒性更敏感。 Rb1 介导的 TOP2 可裂解复合物的加工和修复在基因上与其结合 E2F 和执行 DNA 损伤诱导的细胞周期检查点的能力是分开的。 Rb1 蛋白在完整细胞中结合 TOP2 和 BRCA1，pRb 是 TOP2 和 BRCA1 之间关联所必需的。这些结果表明，pRb 通过将 BRCA1 等蛋白质招募到受损位点，促进 TOP2 可裂解复合物的加工和修复。因此，pRb 的功能状态可能通过促进被捕获的 TOP2-DNA 复合物的修复以及执行细胞周期检查点来影响依托泊苷的敏感性。
Type II topoisomerases (TOP2) introduce transient double-stranded DNA breaks through a covalent TOP2–DNA intermediate. Anticancer agents like etoposide kill cells by trapping covalent TOP2–DNA cleavable complexes. Pathways influencing the repair of cleavable complexes are expected to be major determinants of therapeutic response to etoposide. Rb1 is required to enforce cell cycle checkpoints in response to DNA damage, but evidence for a direct role in the processing and repair of DNA lesions is lacking. We observe that degradation of trapped TOP2-cleavable complexes, liberation of DNA strand breaks, and repair of those breaks occurs more efficiently in cells expressing Rb1 protein (pRb). Cells lacking pRb are more sensitive to etoposide-induced cytotoxicity. Rb1-mediated processing and repair of TOP2-cleavable complexes is genetically separable from its ability to bind E2F and enforce DNA damage-induced cell cycle checkpoints. Rb1 protein binds both TOP2 and BRCA1 in intact cells, and pRb is required for association between TOP2 and BRCA1. These results suggest that pRb facilitates processing and repair of TOP2-cleavable complexes by recruiting proteins like BRCA1 to the damaged site. The functional status of pRb, therefore, may influence sensitivity to etoposide by facilitating the repair of trapped TOP2–DNA complexes as well as by enforcing cell cycle checkpoints.