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Raguz, Nikoleta; Heim, Astrid; Engal, Eden; Wesche, Juste; Merl-Pham, Juliane; Hauck, Stefanie M.; Erkelenz, Steffen; Schaal, Heiner; Bensaude, Olivier; Wolf, Alexander; Salton, Maayan and Boettger, Angelika (2020): JMJD6 Regulates Splicing of Its Own Gene Resulting in Alternatively Spliced Isoforms with Different Nuclear Targets. In: International Journal of Molecular Sciences, Vol. 21, No. 18, 6618

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Jumonji-domain-containing protein 6 (JMJD6) is a Fe(II) and 2-oxogluterate (2OG) dependent oxygenase involved in gene regulation through post-translationally modifying nuclear proteins. It is highly expressed in many cancer types and linked to tumor progression and metastasis. Four alternatively-splicedjmjd6transcripts were annotated. Here, we focus on the two most abundantly expressed ones, which we calljmjd6-2andjmjd6-Ex5.TCGA SpliceSeqdata revealed a significant decrease ofjmjd6-Ex5transcripts in patients and postmortem tissue of several tumors. The two protein isoforms are distinguished by their C-terminal sequences, which include a serine-rich region (polyS-domain) in JMJD6-2 that is not present in JMJD6-Ex5. Immunoprecipitation followed by LC-MS/MS for JMJD6-Ex5 shows that different sets of proteins interact with JMJD6-2 and JMJD6-Ex5 with only a few overlaps. In particular, we found TFIIF-associating CTD phosphatase (FCP1), proteins of the survival of motor neurons (SMN) complex, heterogeneous nuclear ribonucleoproteins (hnRNPs) and upstream binding factor (UBF) to interact with JMJD6-Ex5. Like JMJD6-2, both UBF and FCP1 comprise a polyS-domain. The polyS domain of JMJD6-2 might block the interaction with polyS-domains of other proteins. In contrast, JMJD6-2 interacts with many SR-like proteins with arginine/serine-rich (RS)-domains, including several splicing factors. In an HIV-based splicing reporter assay, co-expression of JMJD6-2 inhibited exon inclusion, whereas JMJD6-Ex5 did not have any effect. Furthermore, the silencing ofjmjd6by siRNAs favoredjmjd6-Ex5transcripts, suggesting that JMJD6 controls splicing of its own pre-mRNA. The distinct molecular properties of JMJD6-2 and JMJD6-Ex5 open a lead into the functional implications of the variations of their relative abundance in tumors.

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