Proteomics

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Tumour mutations in long noncoding RNAs enhance cell fitness


ABSTRACT: Tumour DNA contains thousands of somatic single nucleotide variants (SNVs) in non-protein-coding elements, yet their functional significance remains poorly understood. Amongst the most highly mutated elements are long noncoding RNAs (lncRNAs), functional transcripts with known roles in carcinogenesis. To search for driver mutations in lncRNAs, we apply an integrative driver discovery algorithm to SNVs from 2583 primary tumours and 3527 metastases to reveal 54 potential “driver lncRNAs”. Our algorithm confirms a particularly high mutation rate in the iconic cancer lncRNA, NEAT1, which has been ascribed by recent studies to passenger effects. We directly test the functionality of NEAT1 SNVs using in cellulo mutagenesis, identifying discrete regions where mutations reproducibly increase cell proliferation in diverse cell backgrounds, both cancerous and normal. In particular, mutations in the 5’ region alter ribonucleoprotein assembly and boost the population of subnuclear paraspeckles, thus mechanistically linking mutations to cellular proliferation. We then used RNA-pull down followed by mass spectrometry to identify the protein interactor changing between the wild type and mutant form of NEAT1.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

DISEASE(S): Cancer

SUBMITTER: Manfred Heller  

LAB HEAD: Rory Johnson

PROVIDER: PXD034007 | Pride | 2023-07-20

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20210915_Mut1_R1_GB_i01.raw Raw
20210915_Mut1_R1_GB_i02.raw Raw
20210915_Mut1_R1_GB_i03.raw Raw
20210915_Mut1_WT_R1_GB_i01.raw Raw
20210915_Mut1_WT_R1_GB_i02.raw Raw
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Publications

Tumour mutations in long noncoding RNAs enhance cell fitness.

Esposito Roberta R   Lanzós Andrés A   Uroda Tina T   Ramnarayanan Sunandini S   Büchi Isabel I   Polidori Taisia T   Guillen-Ramirez Hugo H   Mihaljevic Ante A   Merlin Bernard Mefi BM   Mela Lia L   Zoni Eugenio E   Hovhannisyan Lusine L   McCluggage Finn F   Medo Matúš M   Basile Giulia G   Meise Dominik F DF   Zwyssig Sandra S   Wenger Corina C   Schwarz Kyriakos K   Vancura Adrienne A   Bosch-Guiteras Núria N   Andrades Álvaro Á   Tham Ai Ming AM   Roemmele Michaela M   Medina Pedro P PP   Ochsenbein Adrian F AF   Ochsenbein Adrian F AF   Riether Carsten C   Kruithof-de Julio Marianna M   Zimmer Yitzhak Y   Medová Michaela M   Stroka Deborah D   Fox Archa A   Johnson Rory R  

Nature communications 20230608 1


Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic "driver" mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positively-selected lncRNAs are significantly enriched  ...[more]

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