The U1 spliceosomal RNA is recurrently mutated in multiple cancers

Shuai, Shimin; Suzuki, Hiromichi; Díaz-Navarro, Ander; Nadeu, Ferran; Kumar, Sachin; Gutiérrez‐Fernández, Ana; Delgado, Julio; Pinyol, Magda; López-Otı́n, Carlos; Puente, Xosé S.; Taylor, Michael D.; Campo, Elı́as; Stein, Lincoln

doi:10.1038/s41586-019-1651-z

Cited by 143 publications

(121 citation statements)

References 49 publications

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“…Similar mutations were reported with a lower frequency in solid tumors [96]. Recently, recurrent hotspot mutations at the third nucleotide of U1 snRNA were found in several cancer types, including in medulloblastoma, with high frequency [97]. Further investigation revealed that hotspot U1 mutations were present in about 50% of sonic hedgehog (SHH) medulloblastomas, which represents one group of medulloblastomas [98].…”

Section: Mutation Of Spliceosomal Components and Cancersupporting

confidence: 59%

Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds

Fujita

Ishizuka

Mitsukawa

et al. 2020

IJMS

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Human transcriptomes are more divergent than genes and contribute to the sophistication of life. This divergence is derived from various isoforms arising from alternative splicing. In addition, alternative splicing regulated by spliceosomal factors and RNA structures, such as the RNA G-quadruplex, is important not only for isoform diversity but also for regulating gene expression. Therefore, abnormal splicing leads to serious diseases such as cancer and neurodegenerative disorders. In the first part of this review, we describe the regulation of divergent transcriptomes using alternative mRNA splicing. In the second part, we present the relationship between the disruption of splicing and diseases. Recently, various compounds with splicing inhibitor activity were established. These splicing inhibitors are recognized as a biological tool to investigate the molecular mechanism of splicing and as a potential therapeutic agent for cancer treatment. Food-derived compounds with similar functions were found and are expected to exhibit anticancer effects. In the final part, we describe the compounds that modulate the messenger RNA (mRNA) splicing process and their availability for basic research and future clinical potential.

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Section: Mutation Of Spliceosomal Components and Cancersupporting

confidence: 59%

Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds

Fujita

Ishizuka

Mitsukawa

et al. 2020

IJMS

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“…Technical shortcomings (such as coverage 'blind spots' in GC-rich promoters and different filtering strategies) may cause genuine drivers to be missed 48 . Therefore, the discovery of non-coding drivers will benefit from technical improvements, including even sequence coverage, longer and accurate reads, and improved variant-calling methods.…”

Section: Discussionmentioning

confidence: 99%

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

Drivers

2020

Nature

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496

590

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Previous large-scale sequencing projects have identified many putative cancer genes, but most efforts have concentrated on mutations and copy-number alterations in protein-coding genes, mainly using wholeexome sequencing and single-nucleotide polymorphism arrays 1-4. Whole-genome sequencing has made it possible to systematically survey non-coding regions for potential driver events, including single-nucleotide variants (SNVs), small insertions and deletions (indels) and larger structural variants. Whole-genome sequencing enables the precise localization of structural variant breakpoints and connections between distinct genomic loci (juxtapositions). Although previous whole-genome sequencing analyses of modestly sized cohorts have revealed candidate non-coding regulatory driver events 8-15 ,

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“…Failure to properly recognize a splice site is often the result of mutations in the splice site sequence and/or of the dysregulation of splicing factor expression in cancer cells. Moreover, mutations in genes encoding core proteins and RNAs of the splicing machinery have recently emerged as oncogenic drivers which promote widespread transcriptome modifications [16,21]. Herein, we review the current knowledge concerning splicing dysregulation in brain tumors, with particular attention paid to pro-oncogenic processes underlying cancer onset and progression.…”

Section: Dysregulation Of Splicing In Human Cancersmentioning

confidence: 99%

“…In addition to mutations in protein coding genes, recent evidence suggests that the dysregulation of splicing in human cancers may also arise from mutations in non-coding RNAs of the spliceosome. Indeed, mutations in U1 snRNA have been identified across several cancer types and were suggested to act as oncogenic drivers [21]. For instance, 28 of the 164 nucleotides (nt) present in the U1 snRNA are recurrently mutated in bladder cancer.…”

Section: Splicing Dysregulation In Brain Tumorsmentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

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Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology.

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The U1 spliceosomal RNA is recurrently mutated in multiple cancers

Cited by 143 publications

References 49 publications

Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds

Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

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