Publications

• LARP7-mediated U6 snRNA modification ensures splicing fidelity and spermatogenesis in mice.

  Wang X., Li Z.T., Yan Y., Lin P., Tang W., Hasler D., Meduri R., Li Y., Hua M.M., Qi H.T., Lin D.H., Shi H.J., Hui J., Li J., Li D., Yang J.H., Lin J., Meister G., Fischer U., Liu M.F.

  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 remain ... >> More

  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. << Less

  Mol. Cell 0:0-0(2020) [PubMed] [EuropePMC]

• The Alazami syndrome-associated protein LARP7 guides U6 small nuclear RNA modification and contributes to splicing robustness.

  Hasler D., Meduri R., Bak M., Lehmann G., Heizinger L., Wang X., Li Z.T., Sement F.M., Bruckmann A., Dock-Bregeon A.C., Merkl R., Kalb R., Grauer E., Kunstmann E., Zavolan M., Liu M.F., Fischer U., Meister G.

  The La-related protein 7 (LARP7) forms a complex with the nuclear 7SK RNA to regulate RNA polymerase II transcription. It has been implicated in cancer and the Alazami syndrome, a severe developmental disorder. Here, we report a so far unknown role of this protein in RNA modification. We show that ... >> More

  The La-related protein 7 (LARP7) forms a complex with the nuclear 7SK RNA to regulate RNA polymerase II transcription. It has been implicated in cancer and the Alazami syndrome, a severe developmental disorder. Here, we report a so far unknown role of this protein in RNA modification. We show that LARP7 physically connects the spliceosomal U6 small nuclear RNA (snRNA) with a distinct subset of box C/D small nucleolar RNAs (snoRNAs) guiding U6 2'-O-methylation. Consistently, these modifications are severely compromised in the absence of LARP7. Although general splicing remains largely unaffected, transcriptome-wide analysis revealed perturbations in alternative splicing in LARP7-depleted cells. Importantly, we identified defects in 2'-O-methylation of the U6 snRNA in Alazami syndrome siblings carrying a LARP7 mutation. Our data identify LARP7 as a bridging factor for snoRNA-guided modification of the U6 snRNA and suggest that alterations in splicing fidelity contribute to the etiology of the Alazami syndrome. << Less

  Mol. Cell 0:0-0(2020) [PubMed] [EuropePMC]