Arid5a uses disordered extensions of its core ARID domain for distinct DNA- and RNA-recognition and gene regulation

von Ehr, J.; Oberstrass, L.; Yazgan, E.; Schnaubelt, L. I.; Bluemel, N.; McNicoll, F.; Weigand, J. E.; Zarnack, K.; Mueller-McNicoll, M.; Korn, S. M.; Schlundt, A.

doi:10.1101/2024.02.29.582703

bioRxiv · 10.1101/2024.02.29.582703

Arid5a uses disordered extensions of its core ARID domain for distinct DNA- and RNA-recognition and gene regulation

von Ehr, J.·Oberstrass, L.·Yazgan, E.·Schnaubelt, L. I.·Bluemel, N.·McNicoll, F.·Weigand, J. E.·Zarnack, K.·Mueller-McNicoll, M.·Korn, S. M.·Schlundt, A.

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Abstract

AT-rich interacting domain (ARID)-containing proteins, Arids, are a heterogeneous DNA-binding protein family involved in transcription regulation and chromatin processing. For the member Arid5a, no exact DNA-binding preference has been experimentally defined so far. Additionally, the protein binds to mRNA motifs for transcript stabilization, supposedly through the DNA-binding ARID domain. To date, however, no unbiased RNA motif definition and clear dissection of nucleic acid-binding through the ARID domain have been undertaken. Using NMR-centered biochemistry, we here define the Arid5a DNA preference. Further, high-throughput in vitro binding (RBNS) reveals a consensus RNA-binding motif engaged by the core ARID domain. Finally, transcriptome-wide binding (iCLIP2) reveals that Arid5a has a weak preference for (A)U-rich regions in pre-mRNA transcripts of factors related to RNA processing. We find that the intrinsically disordered regions (IDR) flanking the ARID domain modulate the specificity and affinity of DNA-binding, while they appear crucial for RNA interactions. Ultimately, our data suggest that Arid5a uses its extended ARID domain for bi-functional gene regulation and that the involvement of IDR extensions is a more general feature of Arids in interacting with different nucleic acids at the chromatin-mRNA interface.

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von Ehr, J., Oberstrass, L., Yazgan, E., Schnaubelt, L. I., Bluemel, N., McNicoll, F., Weigand, J. E., Zarnack, K., Mueller-McNicoll, M., Korn, S. M., Schlundt, A.. 2024-03-03. Arid5a uses disordered extensions of its core ARID domain for distinct DNA- and RNA-recognition and gene regulation. https://doi.org/10.1101/2024.02.29.582703

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