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HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing

Preussner, Marco ; Schreiner, Silke ; Hung, Lee-Hsueh ; Porstner, Martina ; Jack, Hans-Martin ; Benes, Vladimir ; Ratsch, Gunnar ; Bindereif, Albrecht


Originalveröffentlichung: (2012) Nucleic Acids Research, 1-13 doi:10.1093/nar/gks221
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URN: urn:nbn:de:hebis:26-opus-86728
URL: http://geb.uni-giessen.de/geb/volltexte/2012/8672/

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Freie Schlagwörter (Englisch): CD45 , hnRNP L/LL (heterogeneous ribonucleoproteins L / L-like) , combinatorial exon splicing , phosphatase activity , immune response
Sammlung: Open Access - Publikationsfonds
Universität Justus-Liebig-Universität Gießen
Institut: Institute of Biochemistry
Fachgebiet 1: Universität, Präsident der JLU
Fachgebiet 2: Biochemie (FB 08)
DDC-Sachgruppe: Biowissenschaften, Biologie
Dokumentart: Aufsatz
Sprache: Deutsch
Erstellungsjahr: 2012
Publikationsdatum: 02.04.2012
Kurzfassung auf Englisch: CD45 encodes a trans-membrane protein-tyrosine phosphatase expressed in diverse cells of the immune system. By combinatorial use of three variable exons 4-6, isoforms are generated that differ in their extracellular domain, thereby modulating phosphatase activity and immune response. Alternative splicing of these CD45 exons involves two heterogeneous ribonucleoproteins, hnRNP L and its cell-type specific paralog hnRNP L-like (LL). To address the complex combinatorial splicing of exons 4-6, we investigated hnRNP L/LL protein expression in human B-cells in relation to CD45 splicing patterns, applying RNA-Seq. In addition, mutational and RNA-binding analyses were carried out in HeLa cells. We conclude that hnRNP LL functions as the major CD45 splicing repressor, with two CA elements in exon 6 as its primary target. In exon 4, one element is targeted by both hnRNP L and LL. In contrast, exon 5 was never repressed on its own and only co-regulated with exons 4 and 6. Stable L/LL interaction requires CD45 RNA, specifically exons 4 and 6. We propose a novel model of combinatorial alternative splicing: HnRNP L and LL cooperate on the CD45 pre-mRNA, bridging exons 4 and 6 and looping out exon 5, thereby achieving full repression of the three variable exons.
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