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The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair
Steven E Guard1, Zachary C Poss1, Christopher C Ebmeier1
1Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA.
Abstract:
The chromosome 21 encoded protein kinase DYRK1A is essential for normal human development. Mutations in DYRK1A underlie a spectrum of human developmental disorders, and increased dosage in trisomy 21 is implicated in Down syndrome related pathologies. DYRK1A regulates a diverse array of cellular processes through physical interactions with substrates and binding partners in various subcellular compartments. Despite recent large-scale protein-protein interaction profiling efforts, DYRK1A interactions specific to different subcellular compartments remain largely unknown, impeding progress toward understanding emerging roles for this kinase. Here, we used immunoaffinity purification and quantitative mass spectrometry to identify nuclear interaction partners of endogenous DYRK1A. This interactome was enriched in DNA damage repair factors, transcriptional elongation factors and E3 ubiquitin ligases. We validated an interaction with RNF169, a factor that promotes homology directed repair upon DNA damage, and found that DYRK1A expression and kinase activity are required for maintenance of 53BP1 expression and subsequent recruitment to DNA damage loci. Further, DYRK1A knock out conferred resistance to ionizing radiation in colony formation assays, suggesting that DYRK1A expression decreases cell survival efficiency in response to DNA damage and points to a tumor suppressive role for this kinase.
Insights
DYRK1A, a protein kinase, interacts with DNA repair factors in the nucleus. Its absence enhances cell survival after DNA damage, suggesting a tumor-suppressive role.
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- DYRK1A (Dual specificity Yak1-related kinase 1A) is crucial for human development and implicated in Down syndrome.
- DYRK1A regulates cellular processes via interactions in various subcellular compartments.
- Nuclear DYRK1A interactions are largely uncharacterized, limiting understanding of its functions.
Purpose of the Study:
- To identify nuclear interaction partners of endogenous DYRK1A.
- To elucidate the role of DYRK1A in DNA damage response pathways.
Main Methods:
- Immunoaffinity purification coupled with quantitative mass spectrometry to identify DYRK1A nuclear interactors.
- Validation of DYRK1A-RNF169 interaction.
- Assessment of DYRK1A's role in DNA damage response and cell survival via knockout and ionizing radiation assays.
Main Results:
- The nuclear DYRK1A interactome is enriched in DNA damage repair factors, transcriptional elongation factors, and E3 ubiquitin ligases.
- DYRK1A interacts with RNF169, a key factor in homology-directed DNA repair.
- DYRK1A kinase activity is necessary for maintaining 53BP1 expression and its recruitment to DNA damage sites.
- DYRK1A knockout confers resistance to ionizing radiation, indicating reduced cell survival efficiency under DNA damage.
Conclusions:
- DYRK1A plays a significant role in the nuclear response to DNA damage.
- DYRK1A's function in DNA repair and its impact on cell survival suggest a potential tumor-suppressive role.
- Targeting DYRK1A could offer therapeutic strategies for DNA damage-related pathologies and cancer treatment.
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