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

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

  • Hasler D Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany.
  • Meduri R Department of Biochemistry, Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany.
  • Bąk M Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
  • Lehmann G Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany.
  • Heizinger L Biochemistry Center Regensburg (BZR), Institute of Biophysics and Physical Biochemistry, University of Regensburg, 93053 Regensburg, Germany.
  • Wang X 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.
  • Li ZT 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.
  • Sement FM Sorbonne Université, Centre National de la Recherche Scientifique (CNRS), Laboratory of Integrative Biology of Marine Models (UMR8227), Station Biologique de Roscoff, 29680 Roscoff, France.
  • Bruckmann A Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany.
  • Dock-Bregeon AC Sorbonne Université, Centre National de la Recherche Scientifique (CNRS), Laboratory of Integrative Biology of Marine Models (UMR8227), Station Biologique de Roscoff, 29680 Roscoff, France.
  • Merkl R Department of Biochemistry, Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany.
  • Kalb R Department of Human Genetics, Biozentrum, University of Würzburg, 97074 Würzburg, Germany.
  • Grauer E Department of Human Genetics, Biozentrum, University of Würzburg, 97074 Würzburg, Germany.
  • Kunstmann E Department of Human Genetics, Biozentrum, University of Würzburg, 97074 Würzburg, Germany.
  • Zavolan M Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
  • Liu MF 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.
  • Fischer U Department of Biochemistry, Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany. Electronic address: utz.fischer@biozentrum.uni-wuerzburg.de.
  • Meister G Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany. Electronic address: gunter.meister@ur.de.
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  • 2020-02-05
Published in:
  • Molecular cell. - 2020
2′-O-methylation
Alazami syndrome
LARP7
RNA binding proteins
U6 snRNA
snRNAs
snoRNAs
splicing
Alternative Splicing
Binding Sites
Cell Line, Tumor
Child
Child, Preschool
Conserved Sequence
Developmental Disabilities
Female
Genetic Predisposition to Disease
HEK293 Cells
Humans
Male
Methylation
Middle Aged
Mutation
Nucleic Acid Conformation
Protein Binding
Protein Interaction Domains and Motifs
RNA, Small Nuclear
Ribonucleoproteins
Spliceosomes
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/202763
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