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LARP7-Mediated U6 snRNA Modification Ensures Splicing Fidelity and Spermatogenesis in Mice.
Molecular Cell ( IF 14.5 ) Pub Date : 2020-02-03 , DOI: 10.1016/j.molcel.2020.01.002
Xin Wang 1 , Zhi-Tong Li 1 , Yue Yan 1 , Penghui Lin 2 , Wei Tang 3 , Daniele Hasler 4 , Rajyalakshmi Meduri 5 , Ye Li 6 , Min-Min Hua 7 , Hui-Tao Qi 1 , Di-Hang Lin 1 , Hui-Juan Shi 8 , Jingyi Hui 1 , Jinsong Li 9 , Dangsheng Li 1 , Jian-Hua Yang 2 , Jinzhong Lin 6 , Gunter Meister 4 , Utz Fischer 5 , Mo-Fang Liu 10
Affiliation  

U6 snRNA, as an essential component of the catalytic core of the pre-mRNA processing spliceosome, is heavily modified post-transcriptionally, with 2'-O-methylation being most common. The role of these modifications in pre-mRNA splicing as well as their physiological function in mammals have remained largely unclear. Here we report that the La-related protein LARP7 functions as a critical cofactor for 2'-O-methylation of U6 in mouse male germ cells. Mechanistically, LARP7 promotes U6 loading onto box C/D snoRNP, facilitating U6 2'-O-methylation by box C/D snoRNP. Importantly, ablation of LARP7 in the male germline causes defective U6 2'-O-methylation, massive alterations in pre-mRNA splicing, and spermatogenic failure in mice, which can be rescued by ectopic expression of wild-type LARP7 but not an U6-loading-deficient mutant LARP7. Our data uncover a novel role of LARP7 in regulating U6 2'-O-methylation and demonstrate the functional requirement of such modification for splicing fidelity and spermatogenesis in mice.

中文翻译:

LARP7介导的U6 snRNA修饰可确保小鼠的剪接保真度和生精能力。

U6 snRNA作为mRNA加工前剪接体催化核心的重要组成部分,在转录后经过大量修饰,最常见的是2'-O-甲基化。这些修饰在前mRNA剪接中的作用及其在哺乳动物中的生理功能仍不清楚。在这里,我们报告La相关蛋白LARP7充当小鼠雄性生殖细胞中U6的2'-O-甲基化的关键辅助因子。从机理上讲,LARP7促进U6加载到盒C / D snoRNP上,通过盒C / D snoRNP促进U6 2'-O-甲基化。重要的是,雄性种系中LARP7的切除会导致U6 2'-O-甲基化缺陷,mRNA前剪接中的大量改变以及小鼠的生精失败,可以通过异位表达野生型LARP7而非U6-来挽救负载不足的突变体LARP7。
更新日期:2020-02-03
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