期刊
SCIENCE ADVANCES
卷 7, 期 39, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf8653
关键词
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资金
- Uehara Memorial Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship for Research Abroad
- European Commission
- European Union [750035]
- Dutch Cancer Society [KWF HUBR 2015-7736]
- Netherlands Organisation for Scientific Research (NWO)
- Oncode Institute
- Dutch Cancer Society
- Netherlands X-omics Initiative
- NWO [184.034.019]
- Marie Curie Actions (MSCA) [750035] Funding Source: Marie Curie Actions (MSCA)
The study reveals a three-step mechanism for G4 unwinding, ensuring stability during DNA replication. This mechanism allows for efficient handling of G4 structures during DNA replication, thereby preventing genome instability.
G-quadruplex (or G4) structures form in guanine- rich DNA sequences and threaten genome stability when not properly resolved. G4 unwinding occurs during S phase via an unknown mechanism. Using Xenopus egg extracts, we define a three-step G4 unwinding mechanism that acts during DNA replication. First, the replicative helicase composed of Cdc45, MCM2-7 and GINS (CMG) stalls at a leading strand G4 structure. Second, the DEAH-box helicase 36 (DHX36) mediates bypass of the CMG past the intact G4 structure, allowing approach of the leading strand to the G4. Third, G4 structure unwinding by the Fanconi anemia complementation group J helicase (FANCJ) enables DNA polymerase to synthesize past the G4 motif. A G4 on the lagging strand template does not stall CMG but still requires DNA replication for unwinding. DHX36 and FANCJ have partially redundant roles, conferring pathway robustness. This previously unknown genome maintenance pathway promotes faithful G4 replication, thereby avoiding genome instability.
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