The synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and recruits DNA-repair complexes to damaged chromatin. PAR degradation by poly(ADP-ribose) glycohydrolase (PARG) is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative lengthening of telomeres (ALT). Proteomic analyses uncover a new role for poly(ADP-ribosyl)ation (PARylation) in regulating the chromatin-assembly factor HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during the G2 phase and is required for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells that is mitigated by re-expression of ATRX, a protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response to ATRX deficiency that pervades ALT cancers.

聚 (ADP-核糖) (PAR) 的合成会重新配置局部染色质环境，并招募 DNA 修复复合物修复受损的染色质。聚（ADP-核糖）糖水解酶（PARG）对 PAR 的降解对于 DNA 修复的进展和完成至关重要。在这里，我们表明抑制 PARG 会破坏支持端粒选择性延长 (ALT) 的同源定向修复 (HDR) 机制。蛋白质组学分析揭示了聚（ADP-核糖基）化（PARylation）在调节 ALT 癌细胞中染色质组装因子 HIRA 中的新作用。我们发现 HIRA 在 G2 期端粒处富集，并且是组蛋白 H3.3 沉积和端粒 DNA 合成所必需的。 HIRA 的消耗会引起 ALT 癌细胞的系统性死亡，这种死亡可以通过 ATRX 的重新表达来减轻，ATRX 是一种在 ALT 肿瘤中经常失活的蛋白质。我们认为，PARylation 使 HIRA 能够在对普遍存在 ALT 癌症的 ATRX 缺陷的适应性反应中发挥重要作用。