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bioRxiv · 10.1101/432757

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

Guard, S. E.·Poss, Z. C.·Ebmeier, C. C.·Pagratis, M.·Taatjes, D. J.·Old, W. M.
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Abstract

Loss of function mutations in the protein kinase DYRK1A lead to a syndromic form of autism spectrum disorder and intellectual disability. Conversely, increased DYRK1A dosage is implicated in atypical brain development and neurocognitive deficits in trisomy 21. DYRK1A regulates a diverse array of cellular processes through kinase dependent and independent interactions with substrates and binding partners. Recent evidence implicates DYRK1A in direct regulation of the transcriptional machinery, but many of the molecular details are not yet known. Furthermore, the landscape of DYRK1A interactions in the nucleus is incomplete, impeding progress toward understanding its function in transcription. Here, we used immunoaffinity purification and mass spectrometry to identify nuclear interaction partners of endogenous DYRK1A. These were 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. We further show that knockout of DYRK1A or treatment with DYRK1A inhibitors in HeLa cells impaired efficient recruitment of 53BP1 to DNA double strand breaks induced by ionizing radiation. This nuclear interactome thus reveals a new role for DYRK1A in DNA damage repair and provides a resource for exploring new functions of DYRK1A in the nucleus.

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Guard, S. E., Poss, Z. C., Ebmeier, C. C., Pagratis, M., Taatjes, D. J., Old, W. M.. 2018-10-02. The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair. https://doi.org/10.1101/432757

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