Human Mre11/Human Rad50/Nbs1 and DNA Ligase IIIα/XRCC1 Protein Complexes Act Together in an Alternative Nonhomologous End Joining Pathway
Human Mre11/Human Rad50/Nbs1 and DNA Ligase IIIα/XRCC1 Protein Complexes Act Together in an Alternative Nonhomologous End Joining Pathway
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DOI：
10.1074/jbc.m111.274159
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发表时间：
2011-09-30
影响因子：
4.8
通讯作者：
Tomkinson, Alan E.
中科院分区：
文献类型：
--
作者：
Della-Maria, Julie;Zhou, Yi;Tomkinson, Alan E.
最近的研究表明，在癌细胞中常见的大量缺失和染色体易位的产生中，存在一种定义不明确的非同源末端连接(ALT-NHEJ)替代途径。在这里，我们描述了与ALT-NHEJ连锁的两个因子，hMre11/hRad50/Nbs1(MRN)和DNA连接酶IIIα/XRCC1之间的相互作用。在主要NHEJ途径缺陷的细胞系中，DNA连接酶IIIα的表达以及MRN和DNA连接酶IIIα/XRCC1之间的关联发生了变化。最值得注意的是，DNA损伤诱导了DNA连接酶IV缺陷细胞中这些因素的关联。MRN与DNA连接酶IIIα/XRCC1相互作用，刺激分子间连接，这些蛋白质一起加入不相容的DNA末端，形成模拟ALT-NHEJ的反应。因此，我们的结果为ALT-NHEJ途径提供了新的机制见解，该途径不仅有助于癌细胞基因组的不稳定性，而且也可能成为治疗的靶点。
Recent studies have implicated a poorly defined alternative pathway of nonhomologous end joining (alt-NHEJ) in the generation of large deletions and chromosomal translocations that are frequently observed in cancer cells. Here, we describe an interaction between two factors, hMre11/hRad50/Nbs1 (MRN) and DNA ligase III alpha/XRCC1, that have been linked with alt-NHEJ. Expression of DNA ligase III alpha and the association between MRN and DNA ligase III alpha/XRCC1 are altered in cell lines defective in the major NHEJ pathway. Most notably, DNA damage induced the association of these factors in DNA ligase IV-deficient cells. MRN interacts with DNA ligase III alpha/XRCC1, stimulating intermolecular ligation, and together these proteins join incompatible DNA ends in a reaction that mimics alt-NHEJ. Thus, our results provide novel mechanistic insights into the alt-NHEJ pathway that not only contributes to genome instability in cancer cells but may also be a therapeutic target.