Polη, a Y-family translesion synthesis polymerase, promotes cellular tolerance of Myc-induced replication stress
Polη, a Y-family translesion synthesis polymerase, promotes cellular tolerance of Myc-induced replication stress
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DOI：
10.1242/jcs.212183
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发表时间：
2018-06-01
影响因子：
4
通讯作者：
Yamashita, Takayuki
中科院分区：
文献类型：
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作者：
Kurashima, Kiminori;Sekimoto, Takayuki;Yamashita, Takayuki
癌前细胞和癌细胞的生长依赖于它们对癌基因诱导的复制应激（RS）的耐受性。跨损伤合成 (TLS) 在各种类型 RS 的细胞耐受中发挥着重要作用，并通过使用专门的聚合酶绕过复制障碍。然而，关于 TLS 聚合酶在癌基因诱导的 RS 中的作用的信息有限。在此，我们报告 Pol eta（一种 Y 家族 TLS 聚合酶）可促进 Myc 诱导的 RS 的细胞耐受。 Pol eta 被招募到 Myc 诱导的 RS 位点，Pol eta 耗尽增强了 Myc 诱导的复制叉减慢和停滞以及随后双链断裂 (DSB) 的产生。催化死亡的 Pol eta 的过度表达也促进了 Myc 诱导的 DSB 形成。在缺乏 Pol eta 的情况下，Myc 诱导的 DSB 形成依赖于 MUS81-EME2（S 期特异性核酸内切酶复合物），并且 MUS81-EME2 和 Pol eta 的同时消耗以协同方式增强 RS 和细胞死亡。总的来说，这些结果表明 Pol eta 在 Myc 诱导的 RS 过程中促进分叉进展，从而帮助细胞耐受由此产生的有害影响。此外，本研究强调了在经历 Myc 诱导的 RS 的细胞中，Pol eta 和 MUS81-EME2 之间存在合成疾病或致死的可能性。
Growth of precancerous and cancer cells relies on their tolerance of oncogene-induced replication stress (RS). Translesion synthesis (TLS) plays an essential role in the cellular tolerance of various types of RS and bypasses replication barriers by employing specialized polymerases. However, limited information is available about the role of TLS polymerases in oncogene-induced RS. Here, we report that Pol eta, a Y-family TLS polymerase, promotes cellular tolerance of Myc-inducedRS. Pol eta was recruited to Myc-induced RS sites, and Pol eta depletion enhanced the Myc-induced slowing and stalling of replication forks and the subsequent generation of double-strand breaks (DSBs). Overexpression of a catalytically dead Pol eta also promoted Myc-induced DSB formation. In the absence of Pol eta, Myc-induced DSB formation depended on MUS81-EME2 (the S-phase-specific endonuclease complex), and concomitant depletion of MUS81-EME2 and Pol eta enhanced RS and cell death in a synergistic manner. Collectively, these results indicate that Pol eta facilitates fork progression during Myc-induced RS, thereby helping cells tolerate the resultant deleterious effects. Additionally, the present study highlights the possibility of a synthetic sickness or lethality between Pol eta and MUS81-EME2 in cells experiencing Myc-induced RS.