Researchers Found A Critical Role of LARP7 in U6 snRNA Modification and Splicing Fidelity during Spermatogenesis

A team of scientists led by Dr. LIU Mofang at the Center for Excellence in Molecular Cell Science-Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, have found a critical role of RNA binding protein LARP7 in U6 snRNA Modification and Splicing Fidelity during Spermatogenesis. This work entitled “LARP7-Mediated U6 snRNA Modification Ensures Splicing Fidelity and Spermatogenesis in Mice” was online published in Molecular Cell on Feb 3, 2020. The work was collaborated with Drs. Gunter Meister (University of Regensburg, Germany), Utz Fischer (University of Würzburg, Germany) and Jian-Hua Yang (Sun Yat-sen University, China).

In eukaryotes, the majority of genes are interrupted by introns, and removal of intron sequences from pre-messenger RNAs (pre-mRNAs) and some long non-coding RNAs is of fundamental importance for gene expression. This process of RNA splicing is carried out by large and dynamic ribonucleoprotein (RNP) complexes, termed as the spliceosome. Main building blocks of the major spliceosome are the 5small nuclear RNPs (snRNPs), i.e. U1, U2, U4, U5 and U6, consisting of the name-giving snRNAs and their associated proteins. Among the 5 spliceosomal snRNAs, U6 is the most conserved one and plays an essential role in catalytic reaction during splicing. U6 is long known to be heavily modified post-transcriptionally with 2¢-O-methylation being most common and many of its modifications are evolutionarily conserved from yeast to human. However, the role of these modifications in pre-mRNA splicing, as well astheir physiological function in mammals, has remained largely unclear.

Researchers discover thatthe RNA binding protein LARP7 functions as a critical cofactor for the 2¢-O-methylation of U6 in mouse male germ cells. LARP7 has previously been shown to associate with 7SK RNA and regulate pol II transcription elongation, whose mutations have been implicated in the Alazami syndrome, a severe developmental disorder. Wang et al. show that LARP7 promotes U6 loading onto box C/D snoRNP, thereby facilitating U6 2¢-O-methylation by box C/D snoRNP. The box C/D snoRNP was previously documented for its activity in the 2¢-O-methylation of ribosomal RNAs. Importantly, they demonstrate that LARP7-mediated U6 modification is functionally required for the fidelity of pre-mRNA splicing in male germ cells and spermatogenesis in mice. These findings uncover a novel role for LARP7 in regulating U6 2¢-O-methylation and indicate the critical importance of such action for splicing fidelity and male germ cell development in mice.

This study was supported by the grants from the Chinese Academy of Sciences, National Natural Science Foundation of China, Ministry of Science and Technology, and Science and Technology Commission of Shanghai Municipality.

 

Contact：mfliu@sibcb.ac.cn