Cotranscriptional exon skipping in the genotoxic stress response
Cotranscriptional exon skipping in the genotoxic stress response
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DOI：
10.1038/nsmb.1912
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发表时间：
2010-11-01
影响因子：
16.8
通讯作者：
Auboeuf, Didier
中科院分区：
文献类型：
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作者：
Dutertre, Martin;Sanchez, Gabriel;Auboeuf, Didier
Pre-mRNA剪接在功能上与转录偶联，基因毒性胁迫可以通过影响延长RNA聚合酶II来增强选择性外显子包合。我们在这里报道了各种基因毒性应激诱导剂，包括喜树碱（CPT），抑制Ewing肉瘤原癌蛋白（EWS）， RNA聚合酶ii相关因子和YB-1，剪接体相关因子之间的相互作用。这导致MDM2基因的几个外显子的共转录跳跃，MDM2基因编码主要的p53泛素连接酶。这种可逆的外显子跳变参与了MDM2表达的调控，这可能有助于p53在应激暴露期间的积累，并在应激消除时迅速关闭。最后，一个剪接敏感微阵列鉴定出许多外显子，这些外显子在CPT和EWS-YB-1耗尽时被跳过。这些数据表明，基因毒性应激诱导的转录和剪接机制之间的通信改变，导致广泛的外显子跳变，并在基因毒性应激反应中起核心作用。
Pre-mRNA splicing is functionally coupled to transcription, and genotoxic stresses can enhance alternative exon inclusion by affecting elongating RNA polymerase II. We report here that various genotoxic stress inducers, including camptothecin (CPT), inhibit the interaction between Ewing's sarcoma proto-oncoprotein (EWS), an RNA polymerase II-associated factor, and YB-1, a spliceosome-associated factor. This results in the cotranscriptional skipping of several exons of the MDM2 gene, which encodes the main p53 ubiquitin ligase. This reversible exon skipping participates in the regulation of MDM2 expression that may contribute to the accumulation of p53 during stress exposure and its rapid shut-off when stress is removed. Finally, a splicing-sensitive microarray identified numerous exons that are skipped in response to CPT and EWS-YB-1 depletion. These data demonstrate genotoxic stress-induced alteration of the communication between the transcriptional and splicing machineries, which results in widespread exon skipping and plays a central role in the genotoxic stress response.