Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA.
Biochim Biophys Acta Mol Cell Res. 2019 Dec;1866(12):118539. doi: 10.1016/j.bbamcr.2019.118539. Epub 2019 Sep 3.
Genome integrity is essential for proper cell function such that genetic instability can result in cellular dysfunction and disease. Mutations in the human genome are not random, and occur more frequently at "hotspot" regions that often co-localize with sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures. Non-B DNA-forming sequences are mutagenic, can stimulate the formation of DNA double-strand breaks, and are highly enriched at mutation hotspots in human cancer genomes. Thus, small molecules that can modulate the conformations of these structure-forming sequences may prove beneficial in the prevention and/or treatment of genetic diseases. Further, the development of molecular probes to interrogate the roles of non-B DNA structures in modulating DNA function, such as genetic instability in cancer etiology are warranted. Here, we discuss reported non-B DNA stabilizers, destabilizers, and probes, recent assays to identify ligands, and the potential biological applications of these DNA structure-modulating molecules.
基因组完整性对于细胞的正常功能至关重要，因此遗传不稳定性可能导致细胞功能障碍和疾病。人类基因组中的突变并非随机发生，而是更频繁地发生在“热点”区域，这些区域通常与能够采用替代（即非 B）DNA 结构的序列共定位。形成非 B 型 DNA 的序列具有诱变作用，可以刺激 DNA 双链断裂的形成，并且在人类癌症基因组中的突变热点处高度富集。因此，能够调节这些结构形成序列构象的小分子可能有助于预防和/或治疗遗传疾病。此外，开发用于研究非 B 型 DNA 结构在调节 DNA 功能（例如癌症发病机制中的遗传不稳定性）中的作用的分子探针也是合理的。在这里，我们讨论了已报道的非 B 型 DNA 稳定剂、解稳定剂和探针、最近用于鉴定配体的测定方法，以及这些 DNA 结构调节剂分子的潜在生物学应用。
