PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA.
PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA.
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DOI：
10.1038/ncomms15110
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发表时间：
2017-04-27
影响因子：
16.6
通讯作者：
Weinstock DM
中科院分区：
文献类型：
--
作者：
Day TA;Layer JV;Cleary JP;Guha S;Stevenson KE;Tivey T;Kim S;Schinzel AC;Izzo F;Doench J;Root DE;Hahn WC;Price BD;Weinstock DM
染色体重排在恶性和非恶性疾病的发病机制中都是必不可少的事件，但影响其形成的因素尚不完全清楚。在这里，我们开发了一种锌指核酸酶转位报告，并筛选出调节人类细胞重排的因素。我们确定UBC9和Rad50是人类细胞类型的染色体重排的抑制因子，53BP1、DDB1和聚(ADP)核糖聚合酶3(PARP3)是染色体重排的启动子。我们将重点放在PARP3上，因为它对小鼠的生存能力是必不可少的，并且具有可药物的催化活性。我们发现，PARP3调节G四链(G4)DNA对DNA损伤的反应，从而抑制非同源末端连接和同源重组的修复。在PARP3−/−细胞中，G4DNA的化学稳定导致广泛的DNA双链断裂和合成致死性。我们提出了一个模型，在该模型中，PARP3抑制G4DNA，并通过多条途径促进DNA修复。染色体重排是一系列疾病发病机制中的关键事件。在这里，作者利用锌指核酸酶易位报告符来确定PARP3是这些事件的调节因子，这些事件发生在富含G四链DNA的位点。
Chromosomal rearrangements are essential events in the pathogenesis of both malignant and nonmalignant disorders, yet the factors affecting their formation are incompletely understood. Here we develop a zinc-finger nuclease translocation reporter and screen for factors that modulate rearrangements in human cells. We identify UBC9 and RAD50 as suppressors and 53BP1, DDB1 and poly(ADP)ribose polymerase 3 (PARP3) as promoters of chromosomal rearrangements across human cell types. We focus on PARP3 as it is dispensable for murine viability and has druggable catalytic activity. We find that PARP3 regulates G quadruplex (G4) DNA in response to DNA damage, which suppresses repair by nonhomologous end-joining and homologous recombination. Chemical stabilization of G4 DNA in PARP3−/− cells leads to widespread DNA double-strand breaks and synthetic lethality. We propose a model in which PARP3 suppresses G4 DNA and facilitates DNA repair by multiple pathways. Chromosomal rearrangements are key events in the pathogenesis of a range of disorders. Here the authors utilize a zinc finger nuclease translocation reporter to identify PARP3 as a regulator of these events at sites enriched for G quadruplex DNA.