Journal
EMBO JOURNAL
Volume 29, Issue 7, Pages 1235-1247Publisher
WILEY
DOI: 10.1038/emboj.2010.19
Keywords
alternative splicing; hnRNP A1; Sam68; SMA; SMN2
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Funding
- Telethon [GGP09154]
- The Associazione Italiana Ricerca sul Cancro (AIRC)
- Istituto Superiore della Sanita [527/B/3A/5]
- Association for International Cancer Research (AICR)
- NIH
- Muscular Dystrophy Association
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [0748749] Funding Source: National Science Foundation
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Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. An almost identical SMN2 gene is unable to compensate for this deficiency because a single C-to-T transition at position +6 in exon-7 causes skipping of the exon by a mechanism not yet fully elucidated. We observed that the C-to-T transition in SMN2 creates a putative binding site for the RNA-binding protein Sam68. RNA pull-down assays and UV-crosslink experiments showed that Sam68 binds to this sequence. In vivo splicing assays showed that Sam68 triggers SMN2 exon-7 skipping. Moreover, mutations in the Sam68-binding site of SMN2 or in the RNA-binding domain of Sam68 completely abrogated its effect on exon-7 skipping. Retroviral infection of dominant-negative mutants of Sam68 that interfere with its RNA-binding activity, or with its binding to the splicing repressor hnRNP A1, enhanced exon-7 inclusion in endogenous SMN2 and rescued SMN protein expression in fibroblasts of SMA patients. Our results thus indicate that Sam68 is a novel crucial regulator of SMN2 splicing. The EMBO Journal (2010) 29, 1235-1247. doi:10.1038/emboj.2010.19; Published online 25 February 2010
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