Heim Astrid, Grimm Christina, Müller Udo, Häußler Simon, Mackeen Mukram M, Merl Juliane, Hauck Stefanie M, Kessler Benedikt M, Schofield Christopher J, Wolf Alexander, Böttger Angelika
Department of Biology II, Ludwig Maximilians University, Munich, Großhaderner Strasse 2, 82152 Planegg-Martinsried, Germany.
Chemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK Research Unit Protein Science, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
Nucleic Acids Res. 2014 Jul;42(12):7833-50. doi: 10.1093/nar/gku488. Epub 2014 Jun 9.
The Fe(II) and 2-oxoglutarate dependent oxygenase Jmjd6 has been shown to hydroxylate lysine residues in the essential splice factor U2 auxiliary factor 65 kDa subunit (U2AF65) and to act as a modulator of alternative splicing. We describe further evidence for the role of Jmjd6 in the regulation of pre-mRNA processing including interactions of Jmjd6 with multiple arginine-serine-rich (RS)-domains of SR- and SR-related proteins including U2AF65, Luc7-like protein 3 (Luc7L3), SRSF11 and Acinus S', but not with the bona fide RS-domain of SRSF1. The identified Jmjd6 target proteins are involved in different mRNA processing steps and play roles in exon dependent alternative splicing and exon definition. Moreover, we show that Jmjd6 modifies splicing of a constitutive splice reporter, binds RNA derived from the reporter plasmid and punctually co-localises with nascent RNA. We propose that Jmjd6 exerts its splice modulatory function by interacting with specific SR-related proteins during splicing in a RNA dependent manner.
已证明依赖于Fe(II)和2-氧代戊二酸的加氧酶Jmjd6可使必需剪接因子U2辅助因子65 kDa亚基（U2AF65）中的赖氨酸残基羟基化，并作为可变剪接的调节因子。我们描述了Jmjd6在调节前体mRNA加工中的作用的进一步证据，包括Jmjd6与包括U2AF65、类Luc7蛋白3（Luc7L3）、SRSF11和Acinus S'在内的SR和SR相关蛋白的多个富含精氨酸-丝氨酸（RS）结构域的相互作用，但不与SRSF1的真正RS结构域相互作用。鉴定出的Jmjd6靶蛋白参与不同的mRNA加工步骤，并在外显子依赖性可变剪接和外显子定义中发挥作用。此外，我们表明Jmjd6修饰组成型剪接报告基因的剪接，结合源自报告质粒的RNA，并与新生RNA准时共定位。我们提出Jmjd6在剪接过程中通过以RNA依赖性方式与特定的SR相关蛋白相互作用来发挥其剪接调节功能。
