PuSH - Publication Server of Helmholtz Zentrum München: JMJD6 regulates splicing of its own gene resulting in alternatively spliced isoforms with different nuclear targets.

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Raguz, N. ; Heim, A.* ; Engal, E.* ; Wesche, J. ; Merl-Pham, J. ; Hauck, S.M. ; Erkelenz, S.* ; Schaal, H.* ; Bensaude, O.* ; Wolf, A. ; Salton, M.* ; Böttger, A.*

JMJD6 regulates splicing of its own gene resulting in alternatively spliced isoforms with different nuclear targets.

Int. J. Mol. Sci. 21:6618 (2020)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Splicing ; Polys Domain ; Hydroxylation; Protein 6 Jmjd6; Label-free; Domain; Phosphatase; Receptor; U2af65

ISSN (print) / ISBN 1422-0067

e-ISSN 1661-6596

Journal International Journal of Molecular Sciences

Quellenangaben Volume: 21, Issue: 18, Article Number: 6618

Publisher MDPI

Publishing Place Basel

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Molecular Toxicology and Pharmacology (TOXI)
CF Metabolomics & Proteomics (CF-MPC)

Grants German-Israeli Foundation for Scientific Research and Development