STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes.
STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes.
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STAT3 通过损害 Epstein-Barr 病毒转化的 B 淋巴细胞的同源重组修复来赋予 BRCAness。
DOI：
10.1371/journal.ppat.1008849
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发表时间：
2020-10
期刊：
影响因子：
6.7
通讯作者：
Bhaduri-McIntosh S
中科院分区：
文献类型：
--
作者：
McIntosh MT;Koganti S;Boatwright JL;Li X;Spadaro SV;Brantly AC;Ayers JB;Perez RD;Burton EM;Burgula S;MacCarthy T;Bhaduri-McIntosh S
爱泼斯坦-巴尔病毒(EBV)会导致淋巴瘤和上皮细胞癌。虽然这种广泛流行的病毒在B淋巴细胞中通常是沉默的，但它可以在免疫受损的宿主中引起地方性Burkitt淋巴瘤和移植后淋巴组织增生性疾病/淋巴瘤。通过了解EBV是如何突破细胞增殖障碍的，我们希望破坏这些治疗EBV淋巴瘤和潜在的其他癌症的策略。我们先前已经发现，EB病毒通过激活细胞内的STAT3阻止Chk1的磷酸化，从而抑制S期细胞周期检查点的激活，这是阻止癌基因驱动的增殖的有效屏障。这一观察促使我们研究了DNA修复的后果，因为同源重组修复是最无错误的形式，需要phosphChk1。我们现在报道，Chk1磷酸化的缺陷也抑制了RAD51的核化，从而抑制了DNA双链断裂的同源重组修复。由此产生的对容易出错的微同源介导的末端连接(MMEJ)修复的依赖使EBV转化的细胞容易受到PARP抑制，并同时增加由合成依赖的MMEJ导致的全基因组缺失和插入。对数百种癌症株的转录和药物敏感性数据的分析显示，STAT3依赖的基因集预测癌症对合成致命性PARP抑制的易感性。这些发现：1)展示了肿瘤病毒EBV如何重塑细胞DNA修复；ii)为MMEJ在人类细胞中导致插入提供了第一个全基因组证据；以及iii)扩大了可能对合成致命抑制剂有反应的癌症(EBV相关和无关)的范围，因为STAT3具有成分活性的癌症的高流行率。在基于致癌EB病毒的转化模型中，我们先前证明了细胞癌蛋白STAT3在转化过程中被激活，削弱了ATR对复制应激反应中Chk1的磷酸化能力，从而放松了S阶段的检查点。虽然这种松弛允许EB病毒转化的细胞快速穿过S阶段的检查点，但我们现在表明，STAT3的激活有另一个重要的结果。具体地说，Chk1磷酸化受损会导致同源重组修复受损，这是复制细胞的一种高保真修复形式。结果，EBV转化的增殖细胞变得依赖于容易出错的微同源介导的末端连接(MMEJ)修复，不仅积累了这种修复的缺失，而且还积累了全基因组的插入，并屈服于对MMEJ修复至关重要的PARP的抑制。这些发现还将在人类癌症中常见的STAT3激活与PARP抑制剂的易感性联系起来，同时提供了STAT3基因表达的预测性特征。
Epstein-Barr virus (EBV) causes lymphomas and epithelial cell cancers. Though generally silent in B lymphocytes, this widely prevalent virus can cause endemic Burkitt lymphoma and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. By learning how EBV breaches barriers to cell proliferation, we hope to undermine those strategies to treat EBV lymphomas and potentially other cancers. We had previously found that EBV, through activation of cellular STAT3 prevents phosphorylation of Chk1, and thereby, suppresses activation of the intra-S phase cell-cycle checkpoint, a potent barrier to oncogene-driven proliferation. This observation prompted us to examine the consequences on DNA repair since homologous recombination repair, the most error-free form, requires phosphoChk1. We now report that the defect in Chk1 phosphorylation also curtails RAD51 nucleation, and thereby, homologous recombination repair of DNA double strand breaks. The resulting reliance on error-prone microhomology-mediated end-joining (MMEJ) repair makes EBV-transformed cells susceptible to PARP inhibition and simultaneous accrual of genome-wide deletions and insertions resulting from synthesis-dependent MMEJ. Analysis of transcriptomic and drug susceptibility data from hundreds of cancer lines reveals a STAT3-dependent gene-set predictive of susceptibility of cancers to synthetic lethal PARP inhibition. These findings i) demonstrate how the tumor virus EBV re-shapes cellular DNA repair, ii) provide the first genome-wide evidence for insertions resulting from MMEJ in human cells, and iii) expand the range of cancers (EBV-related and -unrelated) that are likely to respond to synthetic lethal inhibitors given the high prevalence of cancers with constitutively active STAT3. In a transformation model based on the cancer-causing Epstein-Barr virus (EBV), we previously demonstrated that the cellular oncoprotein STAT3, activated during transformation, impairs ATR's ability to phosphorylate Chk1 in response to replication stress, thereby relaxing the intra-S phase checkpoint. While this relaxation allows EBV-transformed cells to rapidly traverse the S phase checkpoint, we now show that activation of STAT3 has another important consequence. Specifically, impaired Chk1 phosphorylation results in impaired homologous recombination repair, a form of high-fidelity repair in replicating cells. As a result, EBV-transformed proliferating cells become dependent on error-prone microhomology mediated end-joining (MMEJ) repair, accumulate not only deletions but also genome-wide insertions from such repair, and succumb to inhibition of PARP, an enzyme critical for MMEJ repair. These findings also link STAT3 activation, commonly observed in human cancers, to PARP inhibitor susceptibility, and simultaneously provide a predictive STAT3 gene expression signature.
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