RNA transcripts regulate G-quadruplex landscapes through G-loop formation

• 成果类型: Article
• 署名作者: Sato, Koichi; Lyu, Jing; van den Berg, Jeroen; Braat, Diana; Cruz, Victoria M.; Navarro Luzon, Carmen; Schimmel, Joost; Esteban-Jurado, Clara; Alemany, Maelys; Dreyer, Jan; Hendrikx, Aiko; Mattiroli, Francesca; van Oudenaarden, Alexander; Tijsterman, Marcel; Elsasser, Simon J.; Knipscheer, Puck
• 署名单位: Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Karolinska Institutet; Karolinska Institutet; Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Leiden University; Leiden University - Excl LUMC
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11942
• DOI: 10.1126/science.adr0493
• 发表日期: 2025-06-12
• 页码: 1225-1231
• 关键词: cytidine deaminase aid; telomeric g-quadruplex; dna-replication; reca protein; homologous recombination; xpf-ercc1 endonuclease; read alignment; cell-cycle; repair; activation

摘要

G-quadruplexes (G4s) are prevalent DNA structures that regulate transcription but also threaten genome stability. How G4 dynamics are controlled remains poorly understood. Here, we report that RNA transcripts govern G4 landscapes through coordinated G-loop assembly and disassembly. G-loop assembly involves activation of the ATM and ATR kinases, followed by homology-directed invasion of RNA opposite the G4 strand mediated by BRCA2 and RAD51. Disassembly of the G-loop resolves the G4 structure through DHX36-FANCJ-mediated G4 unwinding, which triggers nucleolytic incision and subsequent hybrid strand renewal by DNA synthesis. Inhibition of G-loop disassembly causes global G4 and R-loop accumulation, leading to transcriptome dysregulation, replication stress, and genome instability. These findings establish an intricate G-loop assembly-disassembly mechanism that controls G4 landscapes and is essential for cellular homeostasis and survival.