Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Department of Biology, RRC 1021, Emory University, 1510 Clifton Road, NE, Atlanta 30322, GA, USA.
Cell Rep. 2022 Oct 25;41(4):111536. doi: 10.1016/j.celrep.2022.111536.
The "last resort" pathway results in ubiquitylation and degradation of RNA polymerase II in response to transcription stress and is governed by factors such as Def1 in yeast. Here, we show that the SMY2 gene acts as a multi-copy suppressor of DEF1 deletion and functions at multiple steps of the last resort pathway. We also provide genetic and biochemical evidence from disparate cellular processes that Smy2 works more broadly as a hitherto overlooked regulator of Cdc48 function. Similarly, the Smy2 homologs GIGYF1 and -2 affect the transcription stress response in human cells and regulate the function of the Cdc48 homolog VCP/p97, presently being explored as a target for cancer therapy. Indeed, we show that the apoptosis-inducing effect of VCP inhibitors NMS-873 and CB-5083 is GIGYF1/2 dependent.
“最后的手段”途径导致 RNA 聚合酶 II 的泛素化和降解，以响应转录应激，并且受到诸如酵母中 Def1 等因素的控制。在这里，我们表明 SMY2 基因作为 DEF1 缺失的多拷贝抑制子起作用，并在最后的手段途径的多个步骤中起作用。我们还提供了来自不同细胞过程的遗传和生化证据，表明 Smy2 更广泛地作为迄今为止被忽视的 Cdc48 功能调节剂发挥作用。同样，Smy2 同源物 GIGYF1 和 -2 影响人类细胞中的转录应激反应，并调节 Cdc48 同源物 VCP/p97 的功能，目前正在作为癌症治疗的靶点进行探索。事实上，我们表明 VCP 抑制剂 NMS-873 和 CB-5083 的凋亡诱导作用依赖于 GIGYF1/2。
