Cross Cancer Institute and Department of Oncology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Cell Cycle. 2011 Mar 15;10(6):883-94. doi: 10.4161/cc.10.6.14907.
Polycomb group proteins, which have well-established roles in gene regulation, were recently found to accumulate on chromatin surrounding DNA damage and to contribute up to 40 percent of the radiation resistance of cell lines. The oncogenic polycomb protein, BMI-1, was additionally shown to be essential for the increased radiation resistance observed in stem cells and cancer stem cells relative to their more differentiated counterparts. BMI-1, is a very early DNA damage response protein that accumulates through a γH2AX/RNF8-independent, but poly(ADP-ribosyl)ation-dependent mechanism at DNA double-strand breaks. BMI-1 acts together with RING2 and other components of the PRC1 histone H2A E3 ubiquitin ligase to ubiquitylate histones H2A and H2AX in response to DNA damage. BMI-1 dependent ubiquitin modifications are at the base of an ubiquitin pathway that enhances radioresistance through the accumulation of RAP80, 53BP1, and BRCA1. Members of the PRC2 histone H3 lysine 27 methyltransferase complex are also recruited to sites of DSBs but it remains to be determined whether the histone methyltransferase and histone E3 ubiquitin ligase polycomb complexes function in concert or independently during DNA repair. Understanding the contribution of polycomb group proteins to the DNA damage response may lead to novel therapeutic strategies that increase the response of human cancers to therapies that work through DNA damage, while simultaneously sensitizing the cancer stem cell population that would otherwise lead to relapse.
多梳蛋白组蛋白在基因调控中具有既定作用，最近发现它们在围绕 DNA 损伤的染色质上积累，并为细胞系的辐射抗性贡献高达 40%。致癌多梳蛋白 BMI-1 此外还被证明对于干细胞和癌症干细胞中观察到的辐射抗性增加是必不可少的，而与它们更分化的对应物相比。BMI-1 是一种非常早期的 DNA 损伤反应蛋白，通过一种 γH2AX/RNF8 独立但多聚（ADP-核糖基）化依赖的机制在 DNA 双链断裂处积累。BMI-1 与 RING2 和 PRC1 组蛋白 H2A E3 泛素连接酶的其他成分一起作用，以响应 DNA 损伤泛素化组蛋白 H2A 和 H2AX。BMI-1 依赖性泛素修饰是泛素途径的基础，该途径通过 RAP80、53BP1 和 BRCA1 的积累增强了放射抗性。PRC2 组蛋白 H3 赖氨酸 27 甲基转移酶复合物的成员也被招募到 DSB 位点，但仍需确定组蛋白甲基转移酶和组蛋白 E3 泛素连接酶多梳复合物在 DNA 修复过程中是否协同或独立发挥作用。了解多梳蛋白组蛋白对 DNA 损伤反应的贡献可能会导致新的治疗策略，这些策略可以增加人类癌症对通过 DNA 损伤起作用的治疗方法的反应，同时使癌症干细胞群敏感化，否则这些癌症干细胞群会导致复发。
