2. Academic Validation
  3. The Alazami Syndrome-Associated Protein LARP7 Guides U6 Small Nuclear RNA Modification and Contributes to Splicing Robustness

The Alazami Syndrome-Associated Protein LARP7 Guides U6 Small Nuclear RNA Modification and Contributes to Splicing Robustness

  • Mol Cell. 2020 Mar 5;77(5):1014-1031.e13. doi: 10.1016/j.molcel.2020.01.001.
Daniele Hasler 1,  Rajyalakshmi Meduri 2,  Maciej Bąk 3,  Gerhard Lehmann 1,  Leonhard Heizinger 4,  Xin Wang 5,  Zhi-Tong Li 5,  François M Sement 6,  Astrid Bruckmann 1,  Anne-Catherine Dock-Bregeon 6,  Rainer Merkl 2,  Reinhard Kalb 7,  Eva Grauer 7,  Erdmute Kunstmann 7,  Mihaela Zavolan 3,  Mo-Fang Liu 5,  Utz Fischer 8,  Gunter Meister 9
Affiliations

Affiliations

  • 1 Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany.
  • 2 Department of Biochemistry, Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany.
  • 3 Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
  • 4 Biochemistry Center Regensburg (BZR), Institute of Biophysics and Physical Biochemistry, University of Regensburg, 93053 Regensburg, Germany.
  • 5 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.
  • 6 Sorbonne Université, Centre National de la Recherche Scientifique (CNRS), Laboratory of Integrative Biology of Marine Models (UMR8227), Station Biologique de Roscoff, 29680 Roscoff, France.
  • 7 Department of Human Genetics, Biozentrum, University of Würzburg, 97074 Würzburg, Germany.
  • 8 Department of Biochemistry, Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany. Electronic address: utz.fischer@biozentrum.uni-wuerzburg.de.
  • 9 Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany. Electronic address: gunter.meister@ur.de.
PMID: 32017898 DOI: 10.1016/j.molcel.2020.01.001
Abstract

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.

Keywords

2′-O-methylation; Alazami syndrome; LARP7; RNA binding proteins; U6 snRNA; snRNAs; snoRNAs; splicing.

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