Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX deletion from mouse cells altered the repair of telomeric double-strand breaks (DSBs) and induced ALT-like phenotypes, including ALT-associated promyelocytic leukemia (PML) bodies (APBs), telomere sister chromatid exchanges (T-SCEs), and extrachromosomal telomeric signals (ECTSs). Mechanistically, we show that ATRX affects telomeric DSB repair by promoting cohesion of sister telomeres and that loss of ATRX in ALT cells results in diminished telomere cohesion. In addition, we document a role for DAXX in the repair of telomeric DSBs. Removal of telomeric cohesion in combination with DAXX deficiency recapitulates all telomeric DSB repair phenotypes associated with ATRX loss. The data reveal that ATRX has an effect on telomeric DSB repair and that this role involves both telomere cohesion and a DAXX-dependent pathway.

中文翻译：

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ATRX通过促进内聚力和依赖DAXX的活性来影响端粒DSB的修复。

α-地中海贫血/智力低下综合症X连锁染色质重塑剂（ATRX）是DAXX（与死亡域相关的蛋白质）相互作用的蛋白质，通常通过端粒（ALT）替代途径加长在细胞中丢失，但ATRX如何未知损失导致ALT。我们报告说，ATRX从小鼠细胞中的缺失改变了端粒双链断裂（DSBs）的修复并诱导了ALT样表型，包括ALT相关的早幼粒细胞白血病（PML）体（APBs），端粒姐妹染色单体交换（T-SCEs） ，以及染色体外端粒信号（ECTSs）。从机制上讲，我们表明ATRX通过促进端粒的内聚力影响端粒DSB修复，而ALT细胞中ATRX的损失导致端粒内聚力降低。此外，我们记录了DAXX在端粒DSB修复中的作用。端粒凝聚力的消除与DAXX缺乏相结合，概括了与ATRX缺失相关的所有端粒DSB修复表型。数据显示，ATRX对端粒DSB修复有影响，并且该作用涉及端粒内聚和DAXX依赖性途径。