It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved. Replication stress at telomeres promotes the formation of so-called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of factors is required to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions.

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具有挑战性的结局：端粒如何防止脆弱

很明显，复制端粒的困难不仅仅与真核染色体的末端有关。当复制叉进入端粒重复序列时，挑战就已经开始了。遇到的障碍主要包括非规范核酸结构，如果不解决，会干扰复制。端粒的复制压力促进了所谓的脆弱端粒的形成，这些端粒在中期染色体中表现出异常的外观，尽管它们的确切分子性质仍有待阐明。需要大量因素来抵消脆弱性。在这篇综述中，我们提倡端粒脆性不是由复制过程中的初始损伤直接引起的，而是由同源 DNA 重组机制对受损复制叉进行 DNA 修复的次要结果。修复部位的 DNA 合成不完全或部分染色质凝聚可能会随着端粒的脆弱而变得明显。端粒复制过程中的脆弱性和 DNA 修复是一种常见现象，在多种疾病情况下会加剧。