LARP7-Mediated U6 snRNA Modification Ensures Splicing Fidelity and Spermatogenesis in Mice.,Molecular Cell

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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

State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences - University of Chinese Academy of Sciences, Shanghai 200031, China.
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
Animal Core Facility, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
Laboratory for RNA Biology, Biochemistry Center Regensburg (BZR), University of Regensburg, Regensburg, Germany.
Department of Biochemistry, University of Würzburg, 97074 Würzburg, Germany.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China.
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences - University of Chinese Academy of Sciences, Shanghai 200031, China; NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Pharmacy School, Fudan University, Shanghai 200032, China.
NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Pharmacy School, Fudan University, Shanghai 200032, China.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences - University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.

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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