Human Molecular Genetics, 2003, Vol. 12, No. 11 1337-1348
DOI: 10.1093/hmg/ddg136
© 2003 Oxford University Press
HnRNP G and Tra2ß: opposite effects on splicing matched by antagonism in RNA binding
Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK
Received November 6, 2002; Revised March 6, 2003; Accepted March 21, 2003
The hnRNP G family comprises three closely related proteins, hnRNP G, RBMY and hnRNP G-T. We showed previously that they interact with splicing activator proteins, particularly hTra2ß, and suggested that they were involved in regulating Tra2-dependent splicing. We show here that hnRNP G and hTra2ß have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor. HnRNP G acts via a specific sequence to repress the skeletal muscle-specific exon (SK) of human slow skeletal alpha-tropomyosin, TPM3, and stimulates inclusion of the alternative non-muscle exon. The binding of hnRNP G to the exon is antagonized by hTra2ß. The two proteins also have opposite effects upon a dystrophin pseudo-exon. This exon is incorporated in a patient to a higher level in heart muscle than skeletal muscle, causing X-linked dilated cardiomyopathy. It is included to a higher level after transfection of a mini-gene into rodent cardiac myoblasts than into skeletal muscle myoblasts. Co-transfection with hnRNP G represses incorporation in cardiac myoblasts, whereas hTra2ß increases it in skeletal myoblasts. Both the cell specificity and the protein responses depend upon exon sequences. Since the ratio of hnRNP G to Tra2ß mRNA in humans is higher in skeletal muscle than in heart muscle, we propose that the hnRNP G/Tra2ß ratio contributes to the cellular splicing preferences and that the higher proportion of hnRNP G in skeletal muscle plays a role in preventing the incorporation of the pseudo-exon and thus in preventing skeletal muscle dystrophy.
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