Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain; Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain.
Mol Cell. 2015 Feb 5;57(3):506-20. doi: 10.1016/j.molcel.2014.12.026. Epub 2015 Jan 22.
DYRK1A is a dosage-sensitive protein kinase that fulfills key roles during development and in tissue homeostasis, and its dysregulation results in human pathologies. DYRK1A is present in both the nucleus and cytoplasm of mammalian cells, although its nuclear function remains unclear. Genome-wide analysis of DYRK1A-associated loci reveals that the kinase is recruited preferentially to promoters of genes actively transcribed by RNA polymerase II (RNAPII), which are functionally associated with translation, RNA processing, and cell cycle. DYRK1A-bound promoter sequences are highly enriched in a conserved palindromic motif, which is necessary to drive DYRK1A-dependent transcriptional activation. DYRK1A phosphorylates the C-terminal domain (CTD) of RNAPII at Ser2 and Ser5. Depletion of DYRK1A results in reduced association of RNAPII at the target promoters as well as hypophosphorylation of the RNAPII CTD along the target gene bodies. These results are consistent with DYRK1A being a transcriptional regulator by acting as a CTD kinase.
DYRK1A 是一种剂量敏感的蛋白激酶，在发育和组织稳态中发挥关键作用，其失调会导致人类疾病。DYRK1A 存在于哺乳动物细胞的核和细胞质中，但其核功能尚不清楚。对 DYRK1A 相关基因座的全基因组分析表明，该激酶优先被招募到由 RNA 聚合酶 II（RNAPII）转录的基因的启动子上，这些基因与翻译、RNA 处理和细胞周期功能相关。DYRK1A 结合的启动子序列富含一个保守的回文基序，该基序对于驱动 DYRK1A 依赖性转录激活是必需的。DYRK1A 使 RNAPII 的 C 末端结构域（CTD）在 Ser2 和 Ser5 处磷酸化。DYRK1A 的耗竭导致靶启动子上 RNAPII 的结合减少，以及靶基因体内 RNAPII CTD 的低磷酸化。这些结果与 DYRK1A 通过充当 CTD 激酶作为转录调节剂的作用一致。
