当前位置: X-MOL 学术J. Biol. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The extent of cyclin C promoter occupancy directs changes in stress-dependent transcription.
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2020-11-27 , DOI: 10.1074/jbc.ra120.015215
David C Stieg 1 , Katrina F Cooper 1 , Randy Strich 1
Affiliation  

The Cdk8 kinase module (CKM) is a detachable Mediator subunit composed of cyclin C and one each of paralogs Cdk8/Cdk19, Med12/Med12L, and Med13/Med13L. Our previous RNA-Seq studies demonstrated that cyclin C represses a subset of hydrogen peroxide–induced genes under normal conditions but is involved in activating other loci following stress. Here, we show that cyclin C directs this transcriptional reprograming through changes in its promoter occupancy. Following peroxide stress, cyclin C promoter occupancy increased for genes it activates while decreasing at loci it represses under normal conditions. Promoter occupancy of other CKM components generally mirrored cyclin C, indicating that the CKM moves as a single unit. It has previously been shown that some cyclin C leaves the nucleus following cytotoxic stress to induce mitochondrial fragmentation and apoptosis. We observed that CKM integrity appeared compromised at a subset of repressed promoters, suggesting a source of cyclin C that is targeted for nuclear release. Interestingly, mTOR inhibition induced a new pattern of cyclin C promoter occupancy indicating that this control is fine-tuned to the individual stress. Using inhibitors, we found that Cdk8 kinase activity is not required for CKM movement or repression but was necessary for full gene activation. In conclusion, this study revealed that different stress stimuli elicit specific changes in CKM promoter occupancy correlating to altered transcriptional outputs. Finally, although CKM components were recruited or expelled from promoters as a unit, heterogeneity was observed at individual promoters, suggesting a mechanism to generate gene- and stress-specific responses.

中文翻译:

细胞周期蛋白 C 启动子占据的程度指导应激依赖性转录的变化。

Cdk8 激酶模块 (CKM) 是一种可分离的介质亚基,由细胞周期蛋白 C 和旁系同源物 Cdk8/Cdk19、Med12/Med12L 和 Med13/Med13L 各一个组成。我们之前的 RNA-Seq 研究表明,细胞周期蛋白 C 在正常条件下抑制过氧化氢诱导的基因子集,但在应激后参与激活其他基因座。在这里,我们表明细胞周期蛋白 C 通过其启动子占有率的变化指导这种转录重编程。在过氧化物胁迫后,细胞周期蛋白 C 启动子的占有率在它激活的基因中增加,而在正常条件下它抑制的基因座减少。其他 CKM 组分的启动子占有率通常反映细胞周期蛋白 C,表明 CKM 作为一个单元移动。先前已经表明,一些细胞周期蛋白 C 在细胞毒性应激后离开细胞核,诱导线粒体断裂和细胞凋亡。我们观察到 CKM 完整性似乎在被抑制的启动子子集中受到损害,这表明细胞周期蛋白 C 的来源是针对核释放的。有趣的是,mTOR 抑制诱导了一种新的细胞周期蛋白 C 启动子占用模式,表明该控制已针对个体压力进行了微调。使用抑制剂,我们发现 Cdk8 激酶活性不是 CKM 运动或抑制所必需的,而是完整基因激活所必需的。总之,这项研究表明,不同的压力刺激会引起与转录输出改变相关的 CKM 启动子占有率的特定变化。最后,尽管 CKM 组件作为一个单元从发起人中招募或驱逐,
更新日期:2020-11-27
down
wechat
bug