Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, via Selmi 3, 40126 Bologna, Italy.
Nucleic Acids Res. 2020 Dec 2;48(21):11942-11957. doi: 10.1093/nar/gkaa944.
Genomic DNA and cellular RNAs can form a variety of non-B secondary structures, including G-quadruplex (G4) and R-loops. G4s are constituted by stacked guanine tetrads held together by Hoogsteen hydrogen bonds and can form at key regulatory sites of eukaryote genomes and transcripts, including gene promoters, untranslated exon regions and telomeres. R-loops are 3-stranded structures wherein the two strands of a DNA duplex are melted and one of them is annealed to an RNA. Specific G4 binders are intensively investigated to discover new effective anticancer drugs based on a common rationale, i.e.: the selective inhibition of oncogene expression or specific impairment of telomere maintenance. However, despite the high number of known G4 binders, such a selective molecular activity has not been fully established and several published data point to a different mode of action. We will review published data that address the close structural interplay between G4s and R-loops in vitro and in vivo, and how these interactions can have functional consequences in relation to G4 binder activity. We propose that R-loops can play a previously-underestimated role in G4 binder action, in relation to DNA damage induction, telomere maintenance, genome and epigenome instability and alterations of gene expression programs.
基因组 DNA 和细胞 RNA 可以形成多种非 B 型二级结构，包括 G-四链体 (G4) 和 R 环。G4 由由 Hoogsteen 氢键连接的堆叠鸟嘌呤四联体组成，可在真核生物基因组和转录本的关键调控位点形成，包括基因启动子、非翻译外显子区域和端粒。R 环是由 DNA 双链体的两条链熔化，其中一条与 RNA 退火形成的三链结构。目前正在深入研究特定的 G4 结合剂，以基于共同的原理发现新的有效的抗癌药物，即：选择性抑制癌基因表达或特异性破坏端粒维持。然而，尽管已经发现了大量已知的 G4 结合剂，但这种选择性的分子活性尚未完全建立，并且有几项已发表的数据指向不同的作用模式。我们将回顾已发表的研究数据，这些数据涉及体外和体内 G4 与 R 环之间的紧密结构相互作用，以及这些相互作用如何与 G4 结合剂的活性相关产生功能后果。我们提出，R 环可以在 G4 结合剂的作用中发挥以前被低估的作用，涉及 DNA 损伤诱导、端粒维持、基因组和表观基因组不稳定性以及基因表达程序的改变。
