G-quadruplexes represent unique roadblocks to DNA replication, which tends to stall at these secondary structures. Although G-quadruplexes can be found throughout the genome, telomeres, due to their G-richness, are particularly predisposed to forming these structures and thus represent difficult-to-replicate regions. Here, we demonstrate that exonuclease 1 (EXO1) plays a key role in the resolution of, and replication through, telomeric G-quadruplexes. When replication forks encounter G-quadruplexes, EXO1 resects the nascent DNA proximal to these structures to facilitate fork progression and faithful replication. In the absence of EXO1, forks accumulate at stabilized G-quadruplexes and ultimately collapse. These collapsed forks are preferentially repaired via error-prone end joining as depletion of EXO1 diverts repair away from error-free homology-dependent repair. Such aberrant repair leads to increased genomic instability, which is exacerbated at chromosome termini in the form of dysfunction and telomere loss.

中文翻译：

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G-四链体结构的EXO1切除有助于解析和复制。

G-四链体代表DNA复制的独特障碍，该障碍往往停滞在这些二级结构上。尽管可以在整个基因组中找到G-四链体，但是由于其富含G，端粒特别容易形成这些结构，因此代表了难以复制的区域。在这里，我们证明核酸外切酶1（EXO1）在端粒G-四链体的解析和复制中起着关键作用。当复制叉遇到G-四链体时，EXO1会切除靠近这些结构的新生DNA，以促进复制叉的前进和忠实的复制。在没有EXO1的情况下，叉子会聚集在稳定的G四链体上，并最终崩溃。这些塌陷的货叉优先通过易于出错的末端连接进行修复，因为EXO1的耗尽使修复工作从无错误的依赖同源性的修复工作中分离出来。这种异常修复导致基因组不稳定性增加，在染色体末端以功能障碍和端粒丢失的形式加剧。