Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Cell Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Struct Mol Biol. 2020 Dec;27(12):1152-1164. doi: 10.1038/s41594-020-0512-7. Epub 2020 Oct 12.
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）的合成使局部染色质环境重新配置，并将 DNA 修复复合物募集到受损的染色质上。聚（ADP-核糖）糖基水解酶（PARG）对 PAR 的降解对于 DNA 修复的进展和完成是必不可少的。在这里，我们表明，PARG 的抑制会破坏同源定向修复（HDR）机制，这些机制是端粒的替代性延长（ALT）的基础。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 方面的新作用。我们表明，HIRA 在 G2 期在端粒处富集，并且需要组蛋白 H3.3 的沉积和端粒 DNA 的合成。HIRA 的耗竭会引发 ALT 癌细胞的全身性死亡，而 ATRX 的表达再激活可以减轻这种死亡，ATRX 是一种在 ALT 肿瘤中经常失活的蛋白质。我们提出，PARylation 使 HIRA 能够在广泛存在于 ALT 癌症中的 ATRX 缺陷的适应性反应中发挥其重要作用。
