Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, Utrecht 3584 CT, Netherlands.
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, Utrecht 3584 CH, Netherlands.
Sci Adv. 2021 Sep 24;7(39):eabf8653. doi: 10.1126/sciadv.abf8653.
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.
G-四链体（或 G4）结构形成于富含鸟嘌呤的 DNA 序列中，如果不能正确解决，会威胁到基因组的稳定性。G4 在 S 期通过未知机制解旋。利用非洲爪蟾卵提取物，我们定义了一个在 DNA 复制过程中起作用的三步 G4 解旋机制。首先，由 Cdc45、MCM2-7 和 GINS（CMG）组成的复制解旋酶在一条前导链 G4 结构处停滞。其次，DEAH-box 解旋酶 36（DHX36）介导 CMG 绕过完整的 G4 结构，从而使前导链接近 G4。第三，范可尼贫血互补组 J 解旋酶（FANCJ）解旋 G4 结构，使 DNA 聚合酶能够在前导链 G4 模体处合成。滞后链模板上的 G4 不会使 CMG 停滞，但仍需要 DNA 复制来解旋。DHX36 和 FANCJ 具有部分冗余的作用，赋予了途径的稳健性。这个以前未知的基因组维护途径促进了忠实的 G4 复制，从而避免了基因组不稳定。
