The Alazami Syndrome-Associated Protein LARP7 Guides U6 Small Nuclear RNA Modification and Contributes to Splicing Robustness
| Autor: | Leonhard Heizinger, Eva Grauer, Rainer Merkl, Erdmute Kunstmann, Rajyalakshmi Meduri, Daniele Hasler, Utz Fischer, Reinhard Kalb, François M. Sement, Mo-Fang Liu, Gerhard Lehmann, Astrid Bruckmann, Gunter Meister, Zhi-Tong Li, Xin Wang, Mihaela Zavolan, Anne-Catherine Dock-Bregeon, Maciej Bąk |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
biology 2'-O-methylation Alternative splicing RNA polymerase II RNA-binding protein Cell Biology Cell biology 03 medical and health sciences 0302 clinical medicine 7SK RNA RNA splicing biology.protein Small nucleolar RNA Molecular Biology 030217 neurology & neurosurgery Small nuclear RNA 030304 developmental biology |
| Zdroj: | Molecular Cell. 77:1014-1031.e13 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2020.01.001 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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