DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2
DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2
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DOI：
10.1016/s0960-9822(02)01179-x
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发表时间：
2002-10-01
期刊：
影响因子：
9.2
通讯作者：
de Lange, T
中科院分区：
文献类型：
--
作者：
Smogorzewska, A;Karlseder, J;de Lange, T
背景：端粒是防止染色体末端融合所必需的。在哺乳动物细胞中观察到中期染色体的端-端融合，所述哺乳动物细胞由于端粒相关蛋白的功能降低而具有功能障碍的端粒，并且在经历端粒DNA的广泛磨损的细胞中观察到中期染色体的端-端融合。然而，这些融合的分子本质及其发生机制尚未阐明。结果：我们证明，抑制端粒保护因子TRF 2导致的端粒融合是通过DNA连接酶IV依赖性非同源末端连接（NHEJ）产生的。NHEJ引起一个端粒的C链与另一个端粒的G链的共价连接。由此产生的双着丝粒染色体的断裂导致非相互易位，这是人类癌症的标志。端粒NHEJ发生在DNA复制前后，两个姐妹端粒都参与了反应。端粒融合伴随着3'端粒overhangs.Conclusions的积极降解：功能失调的哺乳动物端粒的主要威胁是降解的3'悬垂和随后的端粒末端连接DNA连接酶IV。端粒融合中NHEJ的参与是矛盾的，因为NHEJ因子Ku 70/80和DNA-PKcs存在于端粒并保护染色体末端免于融合。
Background: Telomeres are required to prevent end-to-end chromosome fusions. End-to-end fusions of metaphase chromosomes are observed in mammalian cells with dysfunctional telomeres due to diminished function of telomere-associated proteins and in cells experiencing extensive attrition of telomeric DNA. However, the molecular nature of these fusions and the mechanism by which they occur have not been elucidated.Results: We document that telomere fusions resulting from inhibition of the telomere-protective factor TRF2 are generated by DNA ligase IV-dependent nonhomologous end joining (NHEJ). NHEJ gives rise to covalent ligation of the C strand of one telomere to the G strand of another. Breakage of the resulting dicentric chromosomes results in nonreciprocal translocations, a hallmark of human cancer. Telomere NHEJ took place before and after DNA replication, and both sister telomeres participated in the reaction. Telomere fusions were accompanied by active degradation of the 3' telomeric overhangs.Conclusions: The main threat to dysfunctional mammalian telomeres is degradation of the 3' overhang and subsequent telomere end-joining by DNA ligase IV. The involvement of NHEJ in telomere fusions is paradoxical since the NHEJ factors Ku70/80 and DNA-PKcs are present at telomeres and protect chromosome ends from fusion.