G-quadruplexes on chromosomal DNA negatively regulat es t opoisomer ase 1 activity

Abstract

Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. P re vious researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. Ho w e v er, the reason f or its retention on chromosomal DNA remained unclear . In this study , w e disco v ered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) str uct ures. G4 str uct ures, formed during tran- scription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relie v ed the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop le v els in cells. A dditionally, the activ ation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors to w ards cancer cells. Our study unco v ers a negativ e regulation mechanism of human Top1 and highlights a no v el pathw a y f or activ ating Top1.