Chromatin-wide Profiling of DYRK1A Reveals a Role as a Gene-Specific RNA Polymerase II CTD Kinase
Chromatin-wide Profiling of DYRK1A Reveals a Role as a Gene-Specific RNA Polymerase II CTD Kinase
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DOI：
10.1016/j.molcel.2014.12.026
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发表时间：
2015-02-05
期刊：
影响因子：
16
通讯作者：
de la Luna, Susana
中科院分区：
文献类型：
--
作者：
Di Vona, Chiara;Bezdan, Daniela;de la Luna, Susana
DYRK1A是一种剂量敏感的蛋白激酶，在发育和组织动态平衡中发挥关键作用，它的失调导致人类病理。DYRK1A存在于哺乳动物细胞的胞核和胞浆中，但其核功能尚不清楚。对DYRK1A相关基因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)主动转录的基因的启动子，这些基因在功能上与翻译、RNA加工和细胞周期相关。DYRK1A结合的启动子序列高度富含在保守的回文基序中，这是驱动DYRK1A依赖的转录激活所必需的。DYRK1A在Ser2和Ser5处磷酸化RNAPII的C-末端结构域(CTD)。DYRK1A的缺失导致RNAPII在目标启动子上的结合减少，以及RNAPII CTD沿着目标基因体的低磷酸化。这些结果与DYRK1A通过作为CTD激酶而作为转录调节因子相一致。
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 palin-dromic 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.