Regions of the genome with the potential to form secondary DNA structures pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. How the replisome detects and responds to secondary structures is poorly understood. Here, we show that a core component of the fork protection complex in the eukaryotic replisome, Timeless, harbours in its C‐terminal region a previously unappreciated DNA‐binding domain that exhibits specific binding to G‐quadruplex (G4) DNA structures. We show that this domain contributes to maintaining processive replication through G4‐forming sequences, and exhibits partial redundancy with an adjacent PARP‐binding domain. Further, this function of Timeless requires interaction with and activity of the helicase DDX11. Loss of both Timeless and DDX11 causes epigenetic instability at G4‐forming sequences and DNA damage. Our findings indicate that Timeless contributes to the ability of the replisome to sense replication‐hindering G4 formation and ensures the prompt resolution of these structures by DDX11 to maintain processive DNA synthesis.

中文翻译：

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Timeless 将 G 四链体检测与 DNA 复制过程中 DDX11 解旋酶的处理结合起来。


基因组中可能形成二级 DNA 结构的区域经常对 DNA 复制构成重大障碍，必须积极管理，以保持遗传和表观遗传的完整性。人们对复制体如何检测和响应二级结构知之甚少。在这里，我们展示了真核复制体中分叉保护复合物的核心成分 Timeless，在其 C 末端区域包含一个以前未被认识到的 DNA 结合域，该域表现出与 G-四链体 (G4) DNA 结构的特异性结合。我们证明该结构域有助于通过 G4 形成序列维持持续复制，并与相邻的 PARP 结合结构域表现出部分冗余。此外，Timeless 的这一功能需要与解旋酶 DDX11 相互作用并具有其活性。 Timeless 和 DDX11 的缺失会导致 G4 形成序列的表观遗传不稳定和 DNA 损伤。我们的研究结果表明，Timeless 有助于复制体感知复制阻碍 G4 形成的能力，并确保 DDX11 迅速解析这些结构，以维持持续的 DNA 合成。