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Research.html
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<!DOCTYPE html>
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<title>Yong-Zhen Xu's Lab, WHU.</title>
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<meta name="Keywords" content="Yong-Zhen Xu,YZ Xu,yongzhen xu,Yong-Zhen Xu,Xu Yongzhen,Xu YZ,徐永镇,yong-zhen xu,xuyongzhen,RNA splicing,YZ Xu splicing"/>
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<a href="http://www.bio.whu.edu.cn/" title="Home of Bio.WHU" target="_blank">Dept. of Biochemistry, CLS, WHU</a>
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<h3>Splicing Proofreading by ATPases/RNA helicases </h3>
<h2><em><img src="figure/research1.png" alt="" width="428" height="161.6" hspace="100" vspace="0" align="right" /> </em></h2>
<blockquote>
<p align="justify" class="STYLE12">We found that spliceosomal ATPase Prp5 modulates branch site fidelity by competing with the stability of the BS : U2 snRNA duplex (<em>Mol Cell </em>2007, <em>MCB </em>2012, <em>Cell Rep </em>2013), and ATPase Prp28 proofreads 5' splice site through the stability of the 5'SS : U6 snRNA duplex (<em>NAR</em> 2013). Recently, we found that protein interactions between splicing factors (Prp5-SF3B1), and between <em>trans</em>cription factor and splicing factor (Prp5-Spt8) are also critical for splicing proofreading at the branch site region (<em>Gene Dev </em>2016, <em>NAR</em> 2020). </p>
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<p align="center" class="STYLE12">.<img src="figure/research2.png" width="900" height="231.4" vspace="0" align="baseline" style="margin-left: 100px;"/></p>
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<h3>SF3B1/Hsh155 disease mutations affect interaction with ATPase Prp5 and result in altered branch site selectivity <br /></h3>
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<p><img src="figure/research3.png" width="450" height="204.7" vspace="10" align="right" /></p>
<p align="justify" class="STYLE12">Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDS) and other cancers. We find that hsh155 mutant alleles in <em>S. cerevisiae</em>, counter parts of frequent SF3B1 mutations in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. Mutations in the Hsh155 HEAT motifs from both human disease and yeast genetic screens alter the physical interaction with Prp5 and branch region specification, and phenocopy mutations in Prp5. The altered physical interaction results in changed loading of the BS–U2 duplex into the SF3B complex during pre-spliceosome formation. These results provide a mechanistic framework to explain the consequences of intron recognition and splicing of SF3B1 mutations found in disease (<em>Gene Dev</em> 2016).</p>
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<h3 class="oneColElsCtr">Conserved TSA and TSB sequences promote <em>Trans</em>-splicing in <em>Drosophila</em></h3>
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<p><img src="figure/research4.png" width="400" height="280.7" vspace="10" align="right" /></p>
<p align="justify" class="STYLE12"><em>Trans</em>-splicing in trypanosomes and nematodes has been characterized and utilizes spliced leader RNA, the mechanism of <em>trans</em>-splicing in higher eukaryotes remains unclear. We found two intronic RNA sequences, TSA and TSB, are critical to promote <em>trans</em>-splicing of <em>Drosophilia mod(mdg4)</em>, a classic <em>trans</em>-spliced gene. In TSA, a 13-nt motif is conserved among <em>Drosophilia</em> species and is essential and sufficient for <em>trans</em>-splicing; in TSB, a conserved secondary structure acts as an enhancer. Deletions of TSA and TSB cause developmental and viability defects in flies. TSA binds U1 snRNP through base-pairing between the conserved motif and U1 snRNA. Compensatory changes in U1 snRNA partially rescue <em>trans</em>-splicing of TSA mutants, demonstrating that U1 recruitment is critical to promote <em>trans</em>-splicing <em>in vivo</em>. The conserved motifs are observed in other <em>trans</em>-spliced genes, including <em>lola</em>; thus, these findings represent a novel and general mechanism of <em>Trans</em>-splicing in high eukaryotes (<em>Gene Dev</em> 2015).</p>
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