Cho Sunghee, Moon Heegyum, Loh Tiing Jen, Oh Hyun Kyung, Williams Darren Reese, Liao D Joshua, Zhou Jianhua, Green Michael R, Zheng Xuexiu, Shen Haihong
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
Hormel Institute, University of Minnesota, Austin, MN, USA.
Biochim Biophys Acta. 2014 Jun;1839(6):517-25. doi: 10.1016/j.bbagrm.2014.03.003. Epub 2014 Mar 14.
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease and a leading cause of infant mortality. Deletions or mutations of SMN1 cause SMA, a gene that encodes a SMN protein. SMN is important for the assembly of Sm proteins onto UsnRNA to UsnRNP. SMN has also been suggested to direct axonal transport of β-actin mRNA in neurons. Humans contain a second SMN gene called SMN2 thus SMA patients produce some SMN but not with sufficient levels. The majority of SMN2 mRNA does not include exon 7. Here we show that increased expression of PSF promotes inclusion of exon 7 in the SMN2 whereas reduced expression of PSF promotes exon 7 skipping. In addition, we present evidence showing that PSF interacts with the GAAGGA enhancer in exon 7. We also demonstrate that a mutation in this enhancer abolishes the effects of PSF on exon 7 splicing. Furthermore we show that the RNA target sequences of PSF and tra2β in exon 7 are partially overlapped. These results lead us to conclude that PSF interacts with an enhancer in exon 7 to promote exon 7 splicing of SMN2 pre-mRNA.
脊髓性肌萎缩症（SMA）是一种常染色体隐性遗传病，也是婴儿死亡的主要原因。SMN1基因的缺失或突变会导致SMA，该基因编码一种SMN蛋白。SMN对于Sm蛋白组装到UsnRNA形成UsnRNP至关重要。也有研究表明，SMN可指导神经元中β-肌动蛋白mRNA的轴突运输。人类含有另一个名为SMN2的SMN基因，因此SMA患者会产生一些SMN，但水平不足。大多数SMN2 mRNA不包含外显子7。在此我们表明，PSF表达增加会促进SMN2中外显子7的包含，而PSF表达降低则会促进外显子7跳跃。此外，我们提供的证据表明，PSF与外显子7中的GAAGGA增强子相互作用。我们还证明，该增强子中的一个突变消除了PSF对外显子7剪接的影响。此外，我们表明PSF和tra2β在外显子7中的RNA靶序列部分重叠。这些结果使我们得出结论，PSF与外显子7中的一个增强子相互作用，以促进SMN2前体mRNA的外显子7剪接。
