The Conserved Transcriptional Activation Activity Identified in Dual-Specificity
Xiuke Ouyang1, Zhuqing Wang1, Bingtong Wu1
1Fang Zongxi Center, MoE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.
Abstract:
Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 (DYRK1) encodes a conserved protein kinase that is indispensable to neuron development. However, whether DYRK1 possesses additional functions apart from kinase function remains poorly understood. In this study, we firstly demonstrated that the C-terminal of ascidian Ciona robusta DYRK1 (CrDYRK1) showed transcriptional activation activity independent of its kinase function. The transcriptional activation activity of CrDYRK1 could be autoinhibited by a repression domain in the N-terminal. More excitingly, both activation and repression domains were retained in HsDYRK1A in humans. The genes, activated by the activation domain of HsDYRK1A, are mainly involved in ion transport and neuroactive ligand-receptor interaction. We further found that numerous mutation sites relevant to the DYRK1A-related intellectual disability syndrome locate in the C-terminal of HsDYRK1A. Then, we identified several specific DNA motifs in the transcriptional regulation region of those activated genes. Taken together, we identified a conserved transcription activation domain in DYRK1 in urochordates and vertebrates. The activation is independent of the kinase activity of DYRK1 and can be repressed by its own N-terminal. Transcriptome and mutation data indicate that the transcriptional activation ability of HsDYRK1A is potentially involved in synaptic transmission and neuronal function related to the intellectual disability syndrome.
Insights
Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 (DYRK1) has a novel function beyond its kinase activity. This protein kinase also acts as a transcription factor, regulating genes involved in neuronal function and intellectual disability.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 (DYRK1) is crucial for neuron development.
- The non-kinase functions of DYRK1 are not well understood.
Purpose of the Study:
- To investigate potential non-kinase functions of DYRK1.
- To identify conserved functional domains and regulatory mechanisms of DYRK1.
- To explore the role of DYRK1's transcriptional activity in neurodevelopmental disorders.
Main Methods:
- Analysis of ascidian Ciona robusta DYRK1 (CrDYRK1) and human HsDYRK1A.
- Assessment of transcriptional activation and repression activities.
- Identification of target genes and DNA motifs using transcriptome data.
- Examination of mutation sites associated with intellectual disability.
Main Results:
- CrDYRK1 possesses C-terminal transcriptional activation activity independent of its kinase function.
- N-terminal repression domain autoinhibits DYRK1's activation.
- HsDYRK1A retains both activation and repression domains, regulating genes involved in ion transport and neuroactive ligand-receptor interactions.
- Mutation sites for DYRK1A-related intellectual disability syndrome are located in the C-terminal domain.
Conclusions:
- DYRK1 possesses a conserved transcription activation domain in urochordates and vertebrates.
- This transcriptional activity is independent of kinase function and subject to autoinhibition.
- DYRK1's transcriptional role is implicated in synaptic transmission and neuronal function relevant to intellectual disability.
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