The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair

Sci Rep. 2019 Apr 25;9(1):6539. doi: 10.1038/s41598-019-42990-5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Nucleus / metabolism*
  • Cell Nucleus / radiation effects
  • Cell Survival / radiation effects
  • DNA Damage*
  • DNA Repair* / radiation effects
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Protein Binding / radiation effects
  • Protein Interaction Maps*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Radiation, Ionizing
  • Tumor Suppressor p53-Binding Protein 1 / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • RNF169 protein, human
  • Ubiquitin-Protein Ligases
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases