Alternative DNA structure formation in the mutagenic human c-MYC promoter.
Alternative DNA structure formation in the mutagenic human c-MYC promoter.
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DOI：
10.1093/nar/gkx100
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发表时间：
2017-05-05
影响因子：
14.9
通讯作者：
Vasquez KM
中科院分区：
文献类型：
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作者：
Del Mundo IMA;Zewail-Foote M;Kerwin SM;Vasquez KM
基因组中的突变“热点”区域容易受到遗传不稳定的影响，这意味着它们与疾病有关。这些热点不是随机的，通常与可能采用替代DNA结构的DNA序列（非b DNA，如H-DNA和G4-DNA）共定位，这些DNA序列已被确定为基因组不稳定性的内源性来源。有一些区域包含重叠的序列，可以形成一个以上的非b DNA结构。在序列中，一个结构对另一个结构的形成/稳定性的影响程度还没有完全了解。为了解决这个问题，我们研究了人类c-MYC癌基因中包含潜在的g4形成和h - dna形成元件的染色体断点热点的寡核苷酸的折叠偏好。我们使用多种技术表征了在g4 - dna稳定K+离子或h - dna稳定Mg2+离子存在下形成的结构。我们发现，在有利于形成H-DNA的条件下，稳定的分子内三联体DNA结构占主导地位；而在富含K+的g4 - dna形成条件下，存在多个未折叠和折叠的物种。因此，在包含可能采用多种结构的序列的有限区域内，在给定条件下只有一种结构占主导地位。H-DNA的优势暗示了这种结构与人类c-MYC癌基因相关的不稳定性。
Mutation ‘hotspot’ regions in the genome are susceptible to genetic instability, implicating them in diseases. These hotspots are not random and often co-localize with DNA sequences potentially capable of adopting alternative DNA structures (non-B DNA, e.g. H-DNA and G4-DNA), which have been identified as endogenous sources of genomic instability. There are regions that contain overlapping sequences that may form more than one non-B DNA structure. The extent to which one structure impacts the formation/stability of another, within the sequence, is not fully understood. To address this issue, we investigated the folding preferences of oligonucleotides from a chromosomal breakpoint hotspot in the human c-MYC oncogene containing both potential G4-forming and H-DNA-forming elements. We characterized the structures formed in the presence of G4-DNA-stabilizing K+ ions or H-DNA-stabilizing Mg2+ ions using multiple techniques. We found that under conditions favorable for H-DNA formation, a stable intramolecular triplex DNA structure predominated; whereas, under K+-rich, G4-DNA-forming conditions, a plurality of unfolded and folded species were present. Thus, within a limited region containing sequences with the potential to adopt multiple structures, only one structure predominates under a given condition. The predominance of H-DNA implicates this structure in the instability associated with the human c-MYC oncogene.