Distinct DNA repair pathways cause genomic instability at alternative DNA structures
Distinct DNA repair pathways cause genomic instability at alternative DNA structures
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DOI：
10.1038/s41467-019-13878-9
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发表时间：
2020-01-13
影响因子：
16.6
通讯作者：
Vasquez, Karen M.
中科院分区：
文献类型：
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作者：
McKinney, Jennifer A.;Wang, Guliang;Vasquez, Karen M.
可选的DNA结构形成序列可以刺激突变，并在人类癌症基因组的突变热点处富含，这可能与疾病病因学有关。然而，所涉及的机制并没有得到很好的描述。在这里，我们发现Z-DNA在酵母和人类细胞中都是诱变的，并且核苷酸切除修复复合体Rad10-Rad1(ERCC1-XPF)和错配修复复合体Msh2-Msh3是Z-DNA诱导酵母和人类细胞遗传不稳定性所必需的。ERCC1-XPF和MSH2-MSH3都与Z-DNA形成序列结合，尽管ERCC1-XPF募集到Z-DNA依赖于MSH2-MSH3。此外，依赖ERCC1-XPF(-)的DNA链断裂发生在人类细胞提取物中Z-DNA形成区域附近，我们在亚分子水平上模拟了这些相互作用。我们提出了一种在真核生物中这些复合体识别和处理Z-DNA的关系，代表了Z-DNA诱导基因组不稳定的机制。
Alternative DNA structure-forming sequences can stimulate mutagenesis and are enriched at mutation hotspots in human cancer genomes, implicating them in disease etiology. However, the mechanisms involved are not well characterized. Here, we discover that Z-DNA is mutagenic in yeast as well as human cells, and that the nucleotide excision repair complex, Rad10-Rad1(ERCC1-XPF), and the mismatch repair complex, Msh2-Msh3, are required for Z-DNA-induced genetic instability in yeast and human cells. Both ERCC1-XPF and MSH2-MSH3 bind to Z-DNA-forming sequences, though ERCC1-XPF recruitment to Z-DNA is dependent on MSH2-MSH3. Moreover, ERCC1-XPF(-)dependent DNA strand-breaks occur near the Z-DNA-forming region in human cell extracts, and we model these interactions at the sub-molecular level. We propose a relationship in which these complexes recognize and process Z-DNA in eukaryotes, representing a mechanism of Z-DNA-induced genomic instability.