Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, 251 Bayview Blvd Baltimore, MD 21224, United States.
Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, 251 Bayview Blvd Baltimore, MD 21224, United States.
Curr Med Chem. 2019;26(16):2881-2897. doi: 10.2174/0929867324666171116123345.
Guanine-rich DNA can fold into highly stable four-stranded DNA structures called G-quadruplexes (G4). In recent years, the G-quadruplex field has blossomed as new evidence strongly suggests that such alternately folded DNA structures are likely to exist in vivo. G4 DNA presents obstacles for the replication machinery, and both eukaryotic DNA helicases and polymerases have evolved to resolve and copy G4 DNA in vivo. In addition, G4-forming sequences are prevalent in gene promoters, suggesting that G4-resolving helicases act to modulate transcription.
We have searched the PubMed database to compile an up-to-date and comprehensive assessment of the field's current knowledge to provide an overview of the molecular interactions of Gquadruplexes with DNA helicases and polymerases implicated in their resolution.
Novel computational tools and alternative strategies have emerged to detect G4-forming sequences and assess their biological consequences. Specialized DNA helicases and polymerases catalytically act upon G4-forming sequences to maintain normal replication and genomic stability as well as appropriate gene regulation and cellular homeostasis. G4 helicases also resolve telomeric repeats to maintain chromosomal DNA ends. Bypass of many G4-forming sequences is achieved by the action of translesion DNS polymerases or the PrimPol DNA polymerase. While the collective work has supported a role of G4 in nuclear DNA metabolism, an emerging field centers on G4 abundance in the mitochondrial genome.
Discovery of small molecules that specifically bind and modulate DNA helicases and polymerases or interact with the G4 DNA structure itself may be useful for the development of anticancer regimes.
富含鸟嘌呤的 DNA 可以折叠成高度稳定的四链 DNA 结构，称为 G-四链体（G4）。近年来，随着新的证据强烈表明这种交替折叠的 DNA 结构可能存在于体内，G-四链体领域蓬勃发展。G4 DNA 为复制机制带来了障碍，真核生物的 DNA 解旋酶和聚合酶都进化到能够在体内解决和复制 G4 DNA。此外，形成 G4 的序列在基因启动子中很普遍，这表明解决 G4 的解旋酶可调节转录。
我们已经在 PubMed 数据库中进行了搜索，以编译该领域当前知识的最新和全面评估，为 G-四链体与涉及其解析的 DNA 解旋酶和聚合酶的分子相互作用提供概述。
新的计算工具和替代策略已经出现，以检测形成 G4 的序列并评估其生物学后果。专门的 DNA 解旋酶和聚合酶催化作用于形成 G4 的序列，以维持正常的复制和基因组稳定性以及适当的基因调控和细胞内稳态。G4 解旋酶还解决端粒重复以维持染色体 DNA 末端。许多形成 G4 的序列通过转位 DNA 聚合酶或 PrimPol DNA 聚合酶的作用而被绕过。虽然集体工作支持 G4 在核 DNA 代谢中的作用，但一个新兴的领域集中在线粒体基因组中的 G4 丰度上。
发现特异性结合和调节 DNA 解旋酶和聚合酶或与 G4 DNA 结构本身相互作用的小分子可能有助于开发抗癌方案。
