TY - JOUR
T1 - RNA transcripts regulate G-quadruplex landscapes through G-loop formation
AU - Sato, Koichi
AU - Lyu, Jing
AU - van den Berg, Jeroen
AU - Braat, Diana
AU - Cruz, Victoria M
AU - Navarro Luzón, Carmen
AU - Schimmel, Joost
AU - Esteban-Jurado, Clara
AU - Alemany, Maëlys
AU - Dreyer, Jan
AU - Hendrikx, Aiko
AU - Mattiroli, Francesca
AU - van Oudenaarden, Alexander
AU - Tijsterman, Marcel
AU - Elsässer, Simon J
AU - Knipscheer, Puck
PY - 2025/6/12
Y1 - 2025/6/12
N2 - 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.
AB - 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.
KW - Humans
KW - Ataxia Telangiectasia Mutated Proteins/genetics
KW - BRCA2 Protein/genetics
KW - DEAD-box RNA Helicases/genetics
KW - DNA Replication
KW - G-Quadruplexes
KW - Genomic Instability
KW - R-Loop Structures
KW - Rad51 Recombinase/metabolism
KW - RNA/chemistry
KW - Transcription, Genetic
KW - Transcriptome
KW - Animals
KW - Xenopus laevis
U2 - 10.1126/science.adr0493
DO - 10.1126/science.adr0493
M3 - Article
C2 - 40504899
SN - 0036-8075
VL - 388
SP - 1225
EP - 1231
JO - Science (New York, N.Y.)
JF - Science (New York, N.Y.)
IS - 6752
ER -