TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres—structures that resemble common fragile sites (CFSs)—but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did not generate fragile telomeres. Collectively, these findings indicate that fragile telomeres can arise from BIR-mediated repair of telomeric DSBs.

中文翻译：

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断裂诱导的复制促进脆弱的端粒形成。

TRF1 通过招募 BLM 解旋酶来促进端粒 DNA 的复制，BLM 解旋酶可以解析滞后链模板上的 G-四链体。缺乏 TRF1 或 BLM 的滞后链端粒形成脆弱的端粒——类似于常见脆弱位点 (CFS) 的结构——但它们是如何形成的尚不清楚。我们报告说，类似于 CFS，BLM 缺陷细胞中的脆弱端粒涉及双链断裂 (DSB) 形成，在这种情况下是由 SLX4/SLX1 核酸酶形成的。DSB 通过 POLD3/POLD4 依赖性断裂诱导复制 (BIR) 进行修复，导致含有保守复制 DNA 的脆弱端粒。BIR 还促进具有 FokI 诱导的端粒 DSB 的细胞中脆弱的端粒形成，以及端粒延长 (ALT) 细胞的替代性延长，这些细胞具有自发的端粒损伤。端粒 DSB 的 BIR 与 PARP1-竞争，LIG3 和 XPF 依赖性替代非同源末端连接 (alt-NHEJ)，它不会产生脆弱的端粒。总的来说，这些发现表明脆弱的端粒可能来自 BIR 介导的端粒 DSB 修复。