Hasler, Daniele and Meduri, Rajyalakshmi and Bąk, Maciej and Lehmann, Gerhard and Heizinger, Leonhard and Wang, Xin and Li, Zhi-Tong and Sement, François M. and Bruckmann, Astrid and Dock-Bregeon, Anne-Catherine and Merkl, Rainer and Kalb, Reinhard and Grauer, Eva and Kunstmann, Erdmute and Zavolan, Mihaela and Liu, Mo-Fang and Fischer, Utz and Meister, Gunter. (2020) The Alazami Syndrome-Associated Protein LARP7 Guides U6 Small Nuclear RNA Modification and Contributes to Splicing Robustness. Molecular Cell, 77 (5). pp. 1014-1031.e13.
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Official URL: https://edoc.unibas.ch/75693/
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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.
Faculties and Departments: | 05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Zavolan) |
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UniBasel Contributors: | Zavolan, Mihaela and Bak, Maciej |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | Cell Press |
ISSN: | 1097-2765 |
e-ISSN: | 1097-4164 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Identification Number: |
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Last Modified: | 23 Nov 2021 16:32 |
Deposited On: | 23 Nov 2021 16:32 |
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