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）的合成重新配置了局部染色质环境，并将 DNA 修复复合物募集到受损染色质。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 (ALT) 替代延长的同源定向修复 (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。我们表明 HIRA 在 G2 阶段在端粒处富集，并且是组蛋白 H3.3 沉积和端粒 DNA 合成所必需的。HIRA 的耗竭引起 ALT 癌细胞的全身性死亡，而 ATRX 是一种在 ALT 肿瘤中经常失活的蛋白质，可减轻这种死亡。