在静止细胞中，P-TEFb 被 Siah1/2 降解。

P-TEFb is degraded by Siah1/2 in quiescent cells.

机构信息

Departments of Medicine, Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.

Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

出版信息

Nucleic Acids Res. 2022 May 20;50(9):5000-5013. doi: 10.1093/nar/gkac291.

P-TEFb, composed of CycT1 and CDK9, regulates the elongation of transcription by RNA polymerase II. In proliferating cells, it is regulated by 7SK snRNA in the 7SK snRNP complex. In resting cells, P-TEFb is absent, because CycT1 is dephosphorylated, released from CDK9 and rapidly degraded. In this study, we identified the mechanism of this degradation. We mapped the ubiquitination and degradation of free CycT1 to its N-terminal region from positions 1 to 280. This region is ubiquitinated at six lysines, where E3 ligases Siah1 and Siah2 bind and degrade these sequences. Importantly, the inhibition of Siah1/2 rescued the expression of free CycT1 in proliferating as well as resting primary cells. We conclude that Siah1/2 are the E3 ligases that bind and degrade the dissociated CycT1 in resting, terminally differentiated, anergic and/or exhausted cells.

P-TEFb 由 CycT1 和 CDK9 组成，通过 RNA 聚合酶 II 调节转录的延伸。在增殖细胞中，它受 7SK snRNA 在 7SK snRNP 复合物中的调控。在静止细胞中，由于 CycT1 去磷酸化，从 CDK9 释放并迅速降解，P-TEFb 不存在。在这项研究中，我们确定了这种降解的机制。我们将游离 CycT1 的泛素化和降解映射到其从位置 1 到 280 的 N 端区域。该区域在六个赖氨酸处被泛素化，E3 连接酶 Siah1 和 Siah2 结合并降解这些序列。重要的是，Siah1/2 的抑制挽救了增殖和静止的原代细胞中游离 CycT1 的表达。我们得出结论，Siah1/2 是结合并降解静止、终末分化、无能和/或耗竭细胞中游离 CycT1 的 E3 连接酶。