DNA Polymerase Eta Prevents Tumor Cell-Cycle Arrest and Cell Death during Recovery from Replication Stress
DNA Polymerase Eta Prevents Tumor Cell-Cycle Arrest and Cell Death during Recovery from Replication Stress
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DOI：
10.1158/0008-5472.can-17-3931
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发表时间：
2018-12-01
期刊：
影响因子：
11.2
通讯作者：
Eckert, Kristin A.
中科院分区：
文献类型：
--
作者：
Barnes, Ryan P.;Tsao, Wei-Chung;Eckert, Kristin A.
肿瘤转化和基因组不稳定是由复制压力，条件减慢或停止DNA复制分叉增强。因此，癌细胞需要多种酶和检查点信号通路来减轻其生存和增殖的复制压力。靶向在复制应激过程中增强癌细胞存活的蛋白是临床策略中的一种新方法，特别是当靶点产生合成致死性时。DNA聚合酶（Pol h）在基因组稳定性中具有许多关键功能，特别是在翻译合成中。在这里，我们证明了内源性Pol h在不直接形成DNA加合物的药物诱导的复制应激下表现出显著的蛋白质诱导作用，并在整个细胞核中形成强烈的焦点。在复制应激过程中，Pol - h缺陷细胞表现出ATR复制检查点的过度激活，并在细胞周期后期停止。在从复制应激中恢复的过程中，Pol - h缺陷细胞继续表现出异常表型，包括细胞周期进展延迟、细胞凋亡和细胞存活。在Pol h缺乏的情况下，ATR的消耗或抑制是合成致死的，特别是当肿瘤细胞被复制应激诱导药物处理时。总之，我们的数据扩展了细胞环境的知识，增加了DNA损伤剂以外的内源性Pol h表达，并证明了Pol h调节是复制应激反应的核心。由于Pol h在几种肿瘤类型中异常表达，我们的研究结果对于开发更有效的化疗方法和确定Pol h和ATR的共抑制作为潜在的治疗策略至关重要。意义：本研究表明复制应激上调肿瘤细胞的Pol h (POLH)，揭示了Pol h在复制应激后肿瘤细胞恢复中的作用。(c) 2018年aacr。
Neoplastic transformation and genome instability are enhanced by replication stress, conditions that slow or stall DNA replication forks. Consequently, cancer cells require multiple enzymes and checkpoint signaling pathways to mitigate replication stress for their viability and proliferation. Targeting proteins that enhance cancer cell survival during replication stress is a recent approach in clinical strategies, especially when targets produce synthetic lethality. DNA polymerase eta (Pol h) has many key functions in genome stability, particularly for translesion synthesis. Here we demonstrate that endogenous Pol h displays significant protein induction and forms intense foci throughout the nucleus in response to replication stress induced by drugs that do not directly form DNA adducts. During replication stress, Pol h-deficient cells displayed hyperactivation of the ATR replication checkpoint and arrested late in the cell cycle. During recovery from replication stress, Pol h-deficient cells continue to display aberrant phenotypes, including delayed cell-cycle progression, apoptosis, and cell survival. Depletion or inhibition of ATR was synthetically lethal with Pol h deficiency, particularly when tumor cells were treated with replication stress-inducing drugs. Together our data expand knowledge of the cellular environments that increase endogenous Pol h expression beyond DNA damaging agents and demonstrate that Pol h regulation is central to the replication stress response. Because Pol h is aberrantly expressed in several tumor types, our results are critical for developing more effective chemotherapy approaches and identify coinhibition of Pol h and ATR as a potential therapeutic strategy.Significance: This study demonstrates that replication stress upregulates Pol h (POLH) in tumor cells and reveals a role for Pol h in tumor cell recovery following replication stress. (C) 2018 AACR.