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在G2期，备用非同源末端连接对辐射诱导的DNA双链断裂的修复作用增强。

Repair of radiation induced DNA double strand breaks by backup NHEJ is enhanced in G2.

作者信息

Wu Wenqi, Wang Minli, Wu Weizhong, Singh Satyendra K, Mussfeldt Tamara, Iliakis George

机构信息

Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Hufelandstr 55, Essen, Germany.

出版信息

DNA Repair (Amst). 2008 Feb 1;7(2):329-38. doi: 10.1016/j.dnarep.2007.11.008. Epub 2007 Dec 26.

DOI:10.1016/j.dnarep.2007.11.008
PMID:18155970
Abstract

In higher eukaryotes DNA double strand breaks (DSBs) are repaired by homologous recombination (HRR) or non-homologous end joining (NHEJ). In addition to the DNA-PK dependent pathway of NHEJ (D-NHEJ), cells employ a backup pathway (B-NHEJ) utilizing Ligase III and PARP-1. The cell cycle dependence and coordination of these pathways is being actively investigated. We examine DSB repair in unperturbed G1 and G2 phase cells using mouse embryo fibroblast (MEF) mutants defective in D-NHEJ and/or HRR. WT and Rad54(-/-) MEFs repair DSBs with similar efficiency in G1 and G2 phase. LIG4(-/-), DNA-PKcs(-/-), and Ku70(-/-) MEFs show more pronounced repair defects in G1 than in G2. LIG4(-/-)/Rad54(-/-) MEFs repair DSBs as efficiently as LIG4(-/-) MEFs suggesting that the increased repair efficiency in G2 relies on enhanced function of B-NHEJ rather than HRR. In vivo and in vitro plasmid end joining assays confirm an enhanced function of B-NHEJ in G2. The results show a new and potentially important cell cycle regulation of B-NHEJ and generate a framework to investigate the mechanistic basis of HRR contribution to DSB repair.

摘要

在高等真核生物中，DNA双链断裂（DSB）通过同源重组（HRR）或非同源末端连接（NHEJ）进行修复。除了NHEJ的DNA-PK依赖性途径（D-NHEJ）外，细胞还利用连接酶III和PARP-1采用一种备用途径（B-NHEJ）。这些途径的细胞周期依赖性和协调性正在积极研究中。我们使用在D-NHEJ和/或HRR方面存在缺陷的小鼠胚胎成纤维细胞（MEF）突变体，研究未受干扰的G1期和G2期细胞中的DSB修复。野生型和Rad54（-/-）MEF在G1期和G2期以相似的效率修复DSB。LIG4（-/-）、DNA-PKcs（-/-）和Ku70（-/-）MEF在G1期比在G2期表现出更明显的修复缺陷。LIG4（-/-）/Rad54（-/-）MEF修复DSB的效率与LIG4（-/-）MEF相同，这表明G2期修复效率的提高依赖于B-NHEJ功能的增强而非HRR。体内和体外质粒末端连接试验证实了G2期B-NHEJ功能的增强。结果显示了B-NHEJ一种新的且潜在重要的细胞周期调控，并为研究HRR对DSB修复贡献的机制基础提供了一个框架。

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