利用 CRISPR 引导的 G-四联体结合蛋白和配体靶向特定 DNA G-四联体

IF 17.3 1区 生物学 Q1 CELL BIOLOGY Nature Cell Biology Pub Date : 2024-07-03 DOI:10.1038/s41556-024-01448-1
Geng Qin, Zhenqi Liu, Jie Yang, Xiaofeng Liao, Chuanqi Zhao, Jinsong Ren, Xiaogang Qu
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引用次数: 0

摘要

尽管 DNA G-四重链(G4)在健康和疾病中的重要性已得到证实,但目前仍缺乏可随时操纵特定 G4 折叠以进行功能分析和治疗的技术。在这里,我们将 G4 稳定蛋白/配体与 CRISPR 结合使用,选择性地促进特定基因组位点内的单个或多个目标 G4 折叠。我们证明,将核蛋白与催化不活跃的 Cas9 融合,可以特异性地稳定癌基因 MYC 和肌肉相关基因 Itga7 启动子中的 G4s 以及端粒 G4s,从而分别导致细胞增殖停滞、抑制成肌细胞分化和细胞衰老。此外,CRISPR 还能赋予与 G4 结合的化合物吡啶二甲酰胺和哒哒司汀以 G4 内选择性。与传统的G4配体相比,CRISPR引导的生物素连接的吡啶二甲酰胺能更精确地研究新G4的生物功能。我们的研究提供的见解将有助于加深对 G4 功能和治疗干预的理解。
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Targeting specific DNA G-quadruplexes with CRISPR-guided G-quadruplex-binding proteins and ligands
Despite the demonstrated importance of DNA G-quadruplexes (G4s) in health and disease, technologies to readily manipulate specific G4 folding for functional analysis and therapeutic purposes are lacking. Here we employ G4-stabilizing protein/ligand in conjunction with CRISPR to selectively facilitate single or multiple targeted G4 folding within specific genomic loci. We demonstrate that fusion of nucleolin with a catalytically inactive Cas9 can specifically stabilize G4s in the promoter of oncogene MYC and muscle-associated gene Itga7 as well as telomere G4s, leading to cell proliferation arrest, inhibition of myoblast differentiation and cell senescence, respectively. Furthermore, CRISPR can confer intra-G4 selectivity to G4-binding compounds pyridodicarboxamide and pyridostatin. Compared with traditional G4 ligands, CRISPR-guided biotin-conjugated pyridodicarboxamide enables a more precise investigation into the biological functionality of de novo G4s. Our study provides insights that will enhance understanding of G4 functions and therapeutic interventions. Qin, Liu and colleagues develop a tool that combines CRISPR technology with G-quadruplex (G4)-stabilizing protein or ligand to specifically target DNA G4 structures. This tool provides better understanding of G4 functions and enables G4-based drug development.
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来源期刊
Nature Cell Biology
Nature Cell Biology 生物-细胞生物学
CiteScore
28.40
自引率
0.90%
发文量
219
审稿时长
3 months
期刊介绍: Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to: -Autophagy -Cancer biology -Cell adhesion and migration -Cell cycle and growth -Cell death -Chromatin and epigenetics -Cytoskeletal dynamics -Developmental biology -DNA replication and repair -Mechanisms of human disease -Mechanobiology -Membrane traffic and dynamics -Metabolism -Nuclear organization and dynamics -Organelle biology -Proteolysis and quality control -RNA biology -Signal transduction -Stem cell biology
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