Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Nucleic Acids Res. 2019 May 21;47(9):4462-4475. doi: 10.1093/nar/gkz162.
The general transcription factor P-TEFb, a master regulator of RNA polymerase (Pol) II elongation, phosphorylates the C-terminal domain (CTD) of Pol II and negative elongation factors to release Pol II from promoter-proximal pausing. We show here that P-TEFb surprisingly inhibits the myoblast differentiation into myotubes, and that P-TEFb and its two positive complexes are eliminated in this process. In contrast, DYRK1A, another CTD kinase known to control transcription of a subset of genes important for development and tissue homeostasis, is found to activate transcription of key myogenic genes. We show that active DYRK1A exists in a complex with the WD40-repeat protein DCAF7 that stabilizes and tethers DYRK1A to Pol II, so that DYRK1A-DCAF7 can co-migrate with and phosphorylate Pol II along the myogenic gene loci. Thus, DCAF7 modulates the kinase signaling output of DYRK1A on Pol II to stimulate myogenic transcription after active P-TEFb function is shut off.
一般转录因子 P-TEFb 是 RNA 聚合酶 (Pol) II 延伸的主要调节因子，它磷酸化 Pol II 的 C 端结构域 (CTD) 和负延伸因子，从而使 Pol II 从启动子近端暂停中释放出来。我们在这里表明，P-TEFb 出人意料地抑制了成肌细胞向肌管的分化，并且在这个过程中 P-TEFb 及其两个正复合物被消除。相比之下，另一种 CTD 激酶 DYRK1A 已知可控制对发育和组织稳态重要的一组基因的转录，它被发现可激活关键的成肌基因的转录。我们表明，活性 DYRK1A 存在于与 WD40 重复蛋白 DCAF7 的复合物中，该复合物稳定并将 DYRK1A 固定在 Pol II 上，以便 DYRK1A-DCAF7 可以与 Pol II 一起共迁移，并沿着成肌基因座磷酸化 Pol II。因此，DCAF7 调节 DYRK1A 在 Pol II 上的激酶信号输出，以在活跃的 P-TEFb 功能关闭后刺激成肌转录。
