{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Pang Y"],"funding":["Shanghai Municipal Health Commission","Shanghai East Hospital","Research Funds for the Central Universities","Shanghai Pudong New Area Health Commission","Natural Science Foundation of Shanghai","National Natural Science Foundation of China"],"pagination":["gkaf939"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12458079"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["53(18)"],"pubmed_abstract":["G-quadruplexes (G4s) are noncanonical DNA structures that promote genomic instability, particularly in α-thalassemia/mental retardation X-linked (ATRX)-deficient gliomas. Although TOP2B has been implicated in chromatin remodeling, its role in G4 resolution remains poorly understood. Here, we identify TOP2B as a previously unrecognized regulator of G4 homeostasis and show that it functionally cooperates with ATRX to facilitate G4 resolution during DNA replication. Disruption of this pathway by CX-5461, a small molecule originally developed as an RNA polymerase I inhibitor, leads to G4 accumulation, replication stress, and DNA damage. Mechanistically, CX-5461 acts as a TOP2B poison that selectively impairs TOP2B binding at G4 sites, alters replication fork dynamics, and induces MRE11-dependent degradation of stalled forks. These effects are strongly enhanced in ATRX-deficient glioma cells, where TOP2B plays a dominant role in G4 regulation. While etoposide similarly induces G4-related DNA damage, it does not affect the ATRX-TOP2B interaction, highlighting CX-5461's unique mechanism. Our findings establish TOP2B as a critical player in G4 resolution, reveal CX-5461's dual function as a TOP2B poison and G4 stabilizer, and propose G4-associated replication stress as a potential therapeutic target in ATRX-deficient gliomas."],"journal":["Nucleic acids research"],"pubmed_title":["ATRX cooperates with TOP2B for replication fork stability and DNA damage response through G-quadruplex regulation."],"pmcid":["PMC12458079"],"funding_grant_id":["82172820","22ZR1466200","2024-DFZD-003S","PWZxq2022-10","22120250457","22120240228","202340112"],"pubmed_authors":["Ji T","Yang Y","Wang R","Liu M","Zhang J","Zhong C","Cheng M","Chen X","Zhang C","Pang Y","Wang J"],"additional_accession":[]},"is_claimable":false,"name":"ATRX cooperates with TOP2B for replication fork stability and DNA damage response through G-quadruplex regulation.","description":"G-quadruplexes (G4s) are noncanonical DNA structures that promote genomic instability, particularly in α-thalassemia/mental retardation X-linked (ATRX)-deficient gliomas. Although TOP2B has been implicated in chromatin remodeling, its role in G4 resolution remains poorly understood. Here, we identify TOP2B as a previously unrecognized regulator of G4 homeostasis and show that it functionally cooperates with ATRX to facilitate G4 resolution during DNA replication. Disruption of this pathway by CX-5461, a small molecule originally developed as an RNA polymerase I inhibitor, leads to G4 accumulation, replication stress, and DNA damage. Mechanistically, CX-5461 acts as a TOP2B poison that selectively impairs TOP2B binding at G4 sites, alters replication fork dynamics, and induces MRE11-dependent degradation of stalled forks. These effects are strongly enhanced in ATRX-deficient glioma cells, where TOP2B plays a dominant role in G4 regulation. While etoposide similarly induces G4-related DNA damage, it does not affect the ATRX-TOP2B interaction, highlighting CX-5461's unique mechanism. Our findings establish TOP2B as a critical player in G4 resolution, reveal CX-5461's dual function as a TOP2B poison and G4 stabilizer, and propose G4-associated replication stress as a potential therapeutic target in ATRX-deficient gliomas.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-03T19:35:34.087Z","creation":"2026-04-30T03:12:18.197Z"},"accession":"S-EPMC12458079","cross_references":{"pubmed":["40990248"],"doi":["10.1093/nar/gkaf939"]}}