DYRK1A
Developmental stage
Expressed in the developing central nervous system. Overexpressed 1.5-fold in fetal Down syndrome brain.
Domain
The polyhistidine repeats act as targeting signals to nuclear speckles.
The histidine-rich domain (HRD) region is intrinsically disordered and promotes the formation of phase-separated liquid droplets that enhance its ability to phosphorylate the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNA Pol II).
Function
Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities (PubMed:20981014, PubMed:21127067, PubMed:23665168, PubMed:30773093, PubMed:8769099). Exhibits a substrate preference for proline at position P+1 and arginine at position P-3 (PubMed:23665168). Plays an important role in double-strand breaks (DSBs) repair following DNA damage (PubMed:31024071). Mechanistically, phosphorylates RNF169 and increases its ability to block accumulation of TP53BP1 at the DSB sites thereby promoting homologous recombination repair (HRR) (PubMed:30773093). Also acts as a positive regulator of transcription by acting as a CTD kinase that mediates phosphorylation of the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A (PubMed:25620562, PubMed:29849146). May play a role in a signaling pathway regulating nuclear functions of cell proliferation (PubMed:14500717). Modulates alternative splicing by phosphorylating the splice factor SRSF6 (By similarity). Has pro-survival function and negatively regulates the apoptotic process (By similarity). Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1 (By similarity). This in turn inhibits p53/TP53 activity and apoptosis (By similarity). Phosphorylates SEPTIN4, SEPTIN5 and SF3B1 at 'Thr-434' (By similarity).
Involvement in disease
Intellectual developmental disorder, autosomal dominant 7
MRD7
A disease characterized by primary microcephaly, severe intellectual disability without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Intellectual disability is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Autophosphorylated on numerous tyrosine residues. Can also autophosphorylate on serine and threonine residues (in vitro).
Sequence Similarities
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MNB/DYRK subfamily.
Tissue Specificity
Ubiquitous. Highest levels in skeletal muscle, testis, fetal lung and fetal kidney.
Cellular localization
- Nucleus
- Nucleus speckle
Alternative names
DYRK, MNB, MNBH, DYRK1A, Dual specificity tyrosine-phosphorylation-regulated kinase 1A, Dual specificity YAK1-related kinase, HP86, Protein kinase minibrain homolog, hMNB