Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease.
Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease.
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DOI：
10.1016/j.molcel.2021.04.028
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发表时间：
2021-06-17
期刊：
影响因子：
16
通讯作者：
Ahel I
中科院分区：
文献类型：
--
作者：
Prokhorova E;Agnew T;Wondisford AR;Tellier M;Kaminski N;Beijer D;Holder J;Groslambert J;Suskiewicz MJ;Zhu K;Reber JM;Krassnig SC;Palazzo L;Murphy S;Nielsen ML;Mangerich A;Ahel D;Baets J;O'Sullivan RJ;Ahel I
ARH3/ADPRHL2 和 PARG 是脊椎动物中逆转 ADP-核糖基化的主要酶，但它们在体内的功能仍不清楚。 ARH3 是唯一能够去除丝氨酸连接的单 (ADP-核糖) (MAR) 的水解酶，但在体外对抗聚 (ADP-核糖) (PAR) 链的效率远低于 PARG。在这里，通过使用 ARH3 缺陷细胞，我们证明内源性 MARylation 在整个细胞周期（包括有丝分裂）中持续存在于染色质上，并且令人惊讶地具有良好的耐受性。相反，持续的 PARylation 具有剧毒，并具有明显的生理效应，特别是对活性转录组蛋白标记，如 H3K9ac 和 H3K27ac。此外，我们揭示了 ARH3 和 PARG 之间的合成致死相互作用，并将 ARH3 的缺失确定为 PARP 抑制剂耐药性的机制，这两者都可以在癌症治疗中利用。最后，我们将研究结果扩展到神经退行性疾病，表明遗传性 ARH3 缺陷的患者会遭受应激诱导的 PARylation 致病性增加，而这种情况可以通过 PARP 抑制来缓解。染色质丝氨酸连接的 MARylation 在整个细胞周期中不断产生 ADP-核糖基化反应由不同的起始和延伸步骤组成 PARG 和 ARH3 抑制在合成上是致命的，因为 PARylation 的积累 ARH3 缺陷会增加 PARPi 抗性，可用于治疗 Prokhorova 等人。研究表明，PARylation（而非 MARylation）的积累对细胞具有剧毒，扰乱 DNA 合成、染色质组织和转录，最终导致 PARP 依赖性细胞死亡。这是 PARG 和 ARH3 在癌症中的综合致死性以及 ARH3/ADPRHL2 缺陷患者神经变性发展的基础。
ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle, including mitosis, and is surprisingly well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition. Chromatin serine-linked MARylation is constantly produced throughout the cell cycle ADP-ribosylation reactions consist of distinct initiation and elongation steps PARG and ARH3 suppression is synthetically lethal because of accumulation of PARylation ARH3 deficiency increases PARPi resistance that can be exploited therapeutically Prokhorova et al. show that accumulation of PARylation, but not MARylation, is highly toxic to the cell, perturbing DNA synthesis, chromatin organization, and transcription and eventually leading to PARP-dependent cell death. This underlies the synthetic lethality between PARG and ARH3 in cancers and the development of neurodegeneration in ARH3/ADPRHL2-deficient patients.
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DOI：
10.1083/jcb.200511061
发表时间：
2006-01-30
期刊：
The Journal of cell biology
影响因子：
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作者：
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影响因子：
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
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影响因子：
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Gibbs-Seymour I;Fontana P;Rack JGM;Ahel I
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