Elevated replication stress is evident at telomeres of about 10-15% of cancer cells, which maintain their telomeres via a homologous recombination (HR)-based mechanism, referred to as alternative lengthening of telomeres (ALT). How ALT cells resolve replication stress to support their growth remains incompletely characterized. Here, we report that CSB (also known as ERCC6) promotes recruitment of HR repair proteins (MRN, BRCA1, BLM and RPA32) and POLD3 to ALT telomeres, a process that requires the ATPase activity of CSB and is controlled by ATM- and CDK2-dependent phosphorylation. Loss of CSB stimulates telomeric recruitment of MUS81 and SLX4, components of the structure-specific MUS81-EME1-SLX1-SLX4 (MUS-SLX) endonuclease complex, suggesting that CSB restricts MUS-SLX-mediated processing of stalled forks at ALT telomeres. Loss of CSB coupled with depletion of SMARCAL1, a chromatin remodeler implicated in catalyzing regression of stalled forks, synergistically promotes not only telomeric recruitment of MUS81 but also the formation of fragile telomeres, the latter of which is reported to arise from fork stalling. These results altogether suggest that CSB-mediated HR repair and SMARCAL1-mediated fork regression cooperate to prevent stalled forks from being processed into fragile telomeres in ALT cells.

中文翻译：

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CSB 与 SMARCAL1 配合维持 ALT 细胞中的端粒稳定性。

约 10-15% 的癌细胞的端粒复制应激明显升高，这些癌细胞通过基于同源重组 (HR) 的机制（称为端粒选择性延长 (ALT)）来维持端粒。ALT 细胞如何解决复制压力以支持其生长仍不完全清楚。在此，我们报告 CSB（也称为 ERCC6）促进 HR 修复蛋白（MRN、BRCA1、BLM 和 RPA32）和 POLD3 向 ALT 端粒的募集，这一过程需要 CSB 的 ATP 酶活性，并由 ATM- 和 CDK2 控制依赖性磷酸化。CSB 的缺失会刺激 MUS81 和 SLX4（结构特异性 MUS81-EME1-SLX1-SLX4 (MUS-SLX) 核酸内切酶复合物的组成部分）的端粒募集，表明 CSB 限制 MUS-SLX 介导的 ALT 端粒停滞叉的加工。CSB 的缺失加上 SMARCAL1（一种染色质重塑因子，与催化停滞叉的回归有关）协同作用，不仅促进 MUS81 端粒的募集，而且促进脆弱端粒的形成，据报道，后者是由叉停滞引起的。这些结果共同表明，CSB 介导的 HR 修复和 SMARCAL1 介导的分叉回归协同作用，防止停滞的分叉在 ALT 细胞中被加工成脆弱的端粒。