Alternatives Spleißen – Prinzipien, funktionelle Konsequenzen und therapeutische Relevanz

Zusammenfassung

Protein-kodierende Gene in höheren Eukaryoten werden zunächst als prä-mRNA transkribiert, in der die kodierenden Bereiche (Exons) noch durch nichtkodierende Bereiche (Introns) getrennt vorliegen. Durch den Spleißprozess werden die Exons miteinander verbunden und so die reife mRNA erzeugt. Im Fall von alternativem Spleißen können Exons wahlweise in die mRNA aufgenommen oder ausgeschlossen werden, was die Bildung mehrerer reifer mRNAs aus einer prä-mRNA ermöglicht. Über 90 % aller humanen Gene werden alternativ gespleißt, so dass alternatives Spleißen maßgeblich zur Vielfalt des Proteoms beiträgt und wichtige regulatorische Funktionen erfüllt. Dies wird durch Mutationen verdeutlicht, die zu einer Störung im (alternativen) Spleißen führen und direkt mit der Ausbildung verschiedener Krankheiten assoziiert sind. Eine gezielte Korrektur dieser fehlregulierten Spleißprozesse stellt ein attraktives Therapiekonzept dar, das in den letzten Jahren zunehmend Beachtung gefunden hat und gegenwärtig in ersten klinischen Studien getestet wird.

Abstract

Protein-coding genes in higher eukaryotes are transcribed as pre-mRNA in which the coding regions (exons) are separated by non-coding segments (introns). The exons are connected to form the mature mRNA in a process called splicing. In the case of alternative splicing an exon can be either included or skipped from the mature transcript leading to formation of several mRNAs from a single pre-mRNA. As over 90 % of all human genes are alternatively spliced, alternative splicing dramatically increases proteome diversity and fulfills important regulatory functions. This is underlined by mutations that interfere with splicing regulation and directly correlate with the formation of several diseases. Correction of these disturbed splicing processes has emerged as a promising therapeutic concept and has led to the development of several drugs that are currently being tested in clinical trials.

Schlüsselwörter

Genexpression - prä-mRNA - alternatives Spleißen - Intron - Exon - Deep-Sequencing - Proteom

Keywords

gene expression - pre-mRNA - alternative splicing - intron - exon - deep sequencing - proteome

• Literatur

• 1 Black DL. Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 2003; 72: 291-336
• 2 Blencowe BJ. Alternative splicing: new insights from global analyses. Cell 2006; 126: 37-47
• 3 Cooper TA, Wan L, Dreyfuss G. RNA and disease. Cell 2009; 136: 777-793
• 4 Hermiston ML, Xu Z, Weiss A. CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol 2003; 21: 107-137
• 5 Heyd F, Lynch KW. Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol Cell 2010; 40: 126-137
• 6 Khoo B, Krainer AR. Splicing therapeutics in SMN2 and APOB. Curr Opin Mol Ther 2009; 11: 108-115
• 7 Maniatis T, Tasic B. Alternative pre-mRNA splicing and proteome expansion in metazoans. Nature 2002; 418: 236-243
• 8 Möröy T, Heyd F. The impact of alternative splicing in vivo: mouse models show the way. RNA 2007; 13: 1155-1171
• 9 Pan Q, Shai O, Lee LJ et al. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 2008; 40: 1413-1415
• 10 Parra MK, Gee S, Mohandas N et al. Efficient in vivo manipulation of alternative pre-mRNA splicing events using antisense morpholinos in mice. J Biol Chem 2011; 286: 6033-6039
• 11 Spitali P, Aartsma-Rus A. Splice modulating therapies for human disease. Cell 2012; 148: 1085-1088
• 12 Tchilian EZ, Beverley PC. Altered CD45 expression and disease. Trends Immunol 2006; 27: 146-153
• 13 Wang GS, Cooper TA. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 2007; 8: 749-761
• 14 Zhang Z, Lotti F, Dittmar K et al. SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 2008; 133: 585-600
• 15 Zhou J, Zheng X, Shen H. Targeting RNA-splicing for SMA treatment. Mol Cells 2012; 33: 223-228