Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining.
Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining.
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DOI：
10.1042/bj20080413
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发表时间：
2009-02-01
期刊：
影响因子：
--
通讯作者：
Lees-Miller SP
中科院分区：
文献类型：
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作者：
Mahaney BL;Meek K;Lees-Miller SP
DNA双链断裂（DSB）被认为是最具细胞毒性的DNA损伤类型。它们可以通过诸如电离辐射（IR）的外部来源、通过诸如拓扑异构酶毒物的化疗药物和通过诸如V（D）J重组的正常生物过程引入。如果不进行修复，DSB会导致细胞死亡。如果错误修复，DSB可能导致染色体易位和基因组不稳定。非同源末端连接（NHEJ）是哺乳动物细胞中修复IR诱导的DSB的主要途径之一。哺乳动物细胞中NHEJ所需的主要蛋白质是Ku异源二聚体，DNA依赖性蛋白激酶（DNA-PKcs）的催化亚基，Artemis，XRCC 4，DNA连接酶IV和XLF（XRCC 4样因子，也称为Cernunnos）。其他蛋白质包括DNA聚合酶μ和λ、多核苷酸激酶（PNK）和沃纳综合征解旋酶（WRN）也可能发挥作用。本文就哺乳动物细胞中NHEJ的机制进行综述，并讨论DNA-PKcs和DNA-PK介导的磷酸化在NHEJ中的作用。
DNA double strand breaks (DSBs) are considered the most cytotoxic type of DNA lesion. They can be introduced by external sources such as ionizing radiation (IR), by chemotherapeutic drugs such as topoisomerase poisons and by normal biological processes such as V(D)J recombination. If left unrepaired, DSBs can cause cell death. If misrepaired, DSBs may lead to chromosomal translocations and genomic instability. One of the major pathways for the repair of IR-induced DSBs in mammalian cells is non-homologous end-joining (NHEJ). The main proteins required for NHEJ in mammalian cells are the Ku heterodimer, the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), Artemis, XRCC4, DNA ligase IV and XLF (XRCC4-like factor, also called Cernunnos). Additional proteins including DNA polymerases μ and λ, polynucleotide kinase (PNK) and the Werner’s Syndrome helicase (WRN) may also play a role. Here, we will review our current understanding of the mechanism of NHEJ in mammalian cells and discuss the roles of DNA-PKcs and DNA-PK-mediated phosphorylation in NHEJ.