Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1) has been implicated in X-chromosome inactivation, imprinting, and DNA damage repair, and mutations in SMCHD1 can cause facioscapulohumeral muscular dystrophy. More recently, SMCHD1 has also been identified as a component of telomeric chromatin. Here, we report that SMCHD1 is required for DNA damage signaling and non-homologous end joining (NHEJ) at unprotected telomeres. Co-depletion of SMCHD1 and the shelterin subunit TRF2 reduced telomeric 3'-overhang removal in time-course experiments, as well as the number of chromosome end fusions. SMCHD1-deficient cells displayed reduced ATM S1981 phosphorylation and diminished formation of γH2AX foci and of 53BP1-containing telomere dysfunction-induced foci (TIFs), indicating defects in DNA damage checkpoint signaling. Removal of TPP1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF2-depleted SMCHD1 knockout cells. Together, these data indicate that SMCHD1 depletion reduces telomere fusions in TRF2-depleted cells due to defects in ATM-dependent checkpoint signaling and that SMCHD1 mediates DNA damage response activation upstream of ATM phosphorylation at uncapped telomeres.

中文翻译：

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SMCHD1 促进 ATM 依赖性 DNA 损伤信号和修复未封端的端粒。

染色体柔性铰链结构域蛋白 1 (SMCHD1) 的结构维持与 X 染色体失活、印记和 DNA 损伤修复有关，SMCHD1 突变可导致面肩肱型肌营养不良症。最近，SMCHD1 也被确定为端粒染色质的一个组成部分。在这里，我们报告 SMCHD1 是未受保护的端粒处 DNA 损伤信号传导和非同源末端连接 (NHEJ) 所必需的。SMCHD1 和shelterin 亚基TRF2 的共同消耗减少了时间过程实验中端粒3'-突出端的去除，以及染色体末端融合的数量。SMCHD1 缺陷细胞表现出 ATM S1981 磷酸化减少和 γH2AX 病灶和含有 53BP1 的端粒功能障碍诱导病灶 (TIF) 的形成减少，表明 DNA 损伤检查点信号的缺陷。TPP1 的去除和 ATR 信号的随后激活挽救了 TRF2 耗尽的 SMCHD1 敲除细胞中的端粒融合事件。总之，这些数据表明，由于 ATM 依赖性检查点信号传导的缺陷，SMCHD1 耗尽减少了 TRF2 耗尽细胞中的端粒融合，并且 SMCHD1 在未加帽的端粒处介导 ATM 磷酸化上游的 DNA 损伤反应激活。