4.8 Article

LARP7-Mediated U6 snRNA Modification Ensures Splicing Fidelity and Spermatogenesis in Mice

期刊

MOLECULAR CELL
卷 77, 期 5, 页码 999-+

出版社

CELL PRESS
DOI: 10.1016/j.molcel.2020.01.002

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资金

  1. National Key R&D Program of China [2017YFA0504400]
  2. National Natural Science Foundation of China [31961133022, 91940305, 31830109, 31821004, 91640201]
  3. Shanghai Municipal Science and Technology Major Project [17JC1420100, 19JC1410200, 2017SHZDZX01]
  4. Chinese Academy of Sciences [XDB19010203]
  5. DFG [Fi 573/20-1, Fi 573/12-1, Me 2064/9-1, SPP 1784]
  6. European Research Council (ERC) [682291]
  7. Bavarian Ministry for Education and Science (BioSysNet)
  8. GSLS
  9. European Research Council (ERC) [682291] Funding Source: European Research Council (ERC)

向作者/读者索取更多资源

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.

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