Polycomb group proteins in the DNA damage response A link between radiation resistance and "stemness"
Polycomb group proteins in the DNA damage response A link between radiation resistance and "stemness"
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DOI：
10.4161/cc.10.6.14907
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发表时间：
2011-03-15
期刊：
影响因子：
4.3
通讯作者：
Hendzel, Michael J.
中科院分区：
文献类型：
--
作者：
Gieni, Randall S.;Ismail, Ismail H.;Hendzel, Michael J.
Polycomb组蛋白在基因调控中具有公认的作用，最近发现其在DNA损伤周围的染色质上积累，并对细胞系的辐射抗性贡献高达40%。此外，致癌多梳蛋白BMI-1被证明是干细胞和癌症干细胞相对于其更分化的对应物中观察到的辐射抗性增加所必需的。BMI-1是一种非常早期的DNA损伤反应蛋白，其在DNA双链断裂时通过γ H2 AX/RNF 8非依赖性但聚（ADP-核糖基）阳离子依赖性机制积累。BMI-1与RING 2和PRC 1组蛋白H2 A E3泛素连接酶的其他组分一起作用，以响应DNA损伤而使组蛋白H2 A和H2 AX泛素化。BMI-1依赖性泛素修饰是泛素途径的基础，其通过RAP 80、53 BP 1和BRCA 1的积累增强辐射抗性。PRC 2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的位点，但仍有待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地发挥作用。了解polycomb组蛋白对DNA损伤反应的贡献可能会导致新的治疗策略，增加人类癌症对通过DNA损伤起作用的治疗的反应，同时使癌症干细胞群体敏感，否则会导致复发。
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 gamma H2AX/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.