Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome.
Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome.
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DOI：
10.1038/ncomms7042
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发表时间：
2015-01-14
影响因子：
16.6
通讯作者：
Koeffler, H. Phillip
中科院分区：
文献类型：
--
作者：
Madan, Vikas;Kanojia, Deepika;Li, Jia;Okamoto, Ryoko;Sato-Otsubo, Aiko;Kohlmann, Alexander;Sanada, Masashi;Grossmann, Vera;Sundaresan, Janani;Shiraishi, Yuichi;Miyano, Satoru;Thol, Felicitas;Ganser, Arnold;Yang, Henry;Haferlach, Torsten;Ogawa, Seishi;Koeffler, H. Phillip
剪接体基因ZRSR2（位于X染色体上）的体细胞突变与骨髓增生异常综合征（MDS）有关。ZRSR2在剪接体组装的早期阶段参与对3΄剪接位点的识别；然而，它在RNA剪接中的确切作用仍不清楚。在这里，我们将ZRSR2描述为次要剪接体（u12依赖性）组装的重要组成部分。shRNA介导的ZRSR2敲低导致u12型内含子剪接受损，MDS骨髓的rna测序显示，ZRSR2活性缺失导致错误剪接增加。这些剪接缺陷包括u12型内含子的保留，而u2型内含子的剪接基本不受影响。ZRSR2缺陷细胞在体外也表现出增殖潜力降低和髓系和红细胞分化的明显改变。这些数据确定了ZRSR2在RNA剪接中的特定作用，并强调了u12型内含子剪接失调是MDS中ZRSR2突变的特征。
Somatic mutations in the spliceosome gene ZRSR2 — located on the X chromosome — are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3΄ splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here, we characterize ZRSR2 as an essential component of the minor spliceosome (U12-dependent) assembly. shRNA mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns, and RNA-Sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns while splicing of the U2-type introns remain mostly unaffected. ZRSR2 deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS.
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影响因子：
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影响因子：
9.8
作者：
Kadri Z;Shimizu R;Ohneda O;Maouche-Chretien L;Gisselbrecht S;Yamamoto M;Romeo PH;Leboulch P;Chretien S
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Chretien S
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20.3
作者：
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通讯作者：
Koeffler, HP