The RNA Binding Protein hnRNP Q Modulates the Utilization of Exon 7 in the Survival Motor Neuron 2 (SMN2) Gene

被引:90
作者
Chen, Hung-Hsi [1 ]
Chang, Jan-Growth [2 ,3 ]
Lu, Ruei-Min [1 ]
Peng, Tsui-Yi [1 ,4 ]
Tarn, Woan-Yuh [1 ]
机构
[1] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan
[2] Kaohsiung Med Univ Hosp, Dept Med Res, Kaohsiung, Taiwan
[3] Kaohsiung Med Univ, Inst Clin Med, Kaohsiung, Taiwan
[4] Natl Tsing Hua Univ, Inst Mol Med, Hsinchu, Taiwan
关键词
D O I
10.1128/MCB.01332-08
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The human SMN2 gene has a C-to-T transition at position +6 of exon 7 and thus produces exon 7-skipping mRNAs. However, we observed an unexpectedly high level of exon 7-containing SMN2 transcripts as well as SMN protein in testis of smn(-/-) SMN2 transgenic mice. Using affinity chromatography, we identified several SMN RNA-associating proteins in mouse testis and human HeLa cells, including hnRNP Q. The major hnRNP Q isoform, Q1, directly bound SMN exon 7 in the vicinity of nucleotide +6. Overexpression of hnRNP Q1 promoted the inclusion of exon 7 in SMN2, probably by activating the use of its upstream 3' splice site. However, the minor isoforms Q2/Q3 could antagonize the activity of hnRNP Q1 and induced exon 7 exclusion. Intriguingly, enhanced exon 7 inclusion was also observed upon concomitant depletion of three hnRNP Q isoforms. Thus, differential expression of hnRNP Q isoforms may result in intricate control of SMN precursor mRNA splicing. Here, we demonstrate that hnRNP Q is a splicing modulator of SMN, further underscoring the potential of hnRNP Q as a therapeutic target for SMA.
引用
收藏
页码:6929 / 6938
页数:10
相关论文
共 47 条
  • [41] Splicing of a critical exon of human survival motor neuron is regulated by a unique silencer element located in the last intron
    Singh, NK
    Singh, NN
    Androphy, EJ
    Singh, RN
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (04) : 1333 - 1346
  • [42] An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy
    Singh, NN
    Androphy, EJ
    Singh, RN
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 315 (02) : 381 - 388
  • [43] Terry DE, 2004, J AM SOC MASS SPECTR, V15, P784, DOI 10.1016/j.jasms.2004.02.005
  • [44] Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number
    Wirth, B
    Brichta, L
    Schrank, B
    Lochmüller, H
    Blick, S
    Baasner, A
    Heller, R
    [J]. HUMAN GENETICS, 2006, 119 (04) : 422 - 428
  • [45] Wirth B, 2006, PROG MOLEC, V44, P109
  • [46] SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2β1
    Young, PJ
    DiDonato, CJ
    Hu, D
    Kothary, R
    Androphy, EJ
    Lorson, CL
    [J]. HUMAN MOLECULAR GENETICS, 2002, 11 (05) : 577 - 587
  • [47] Thermodynamics of the fragile X mental retardation protein RGG box interactions with G quartet forming RNA
    Zanotti, Kimberly J.
    Lackey, Patrick E.
    Evans, Genevieve L.
    Mihailescu, Mihaela-Rita
    [J]. BIOCHEMISTRY, 2006, 45 (27) : 8319 - 8330