4.8 Article

Alternative polyadenylation is a determinant of oncogenic Ras function

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SCIENCE ADVANCES
卷 7, 期 51, 页码 -

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AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abh0562

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资金

  1. Canadian Institutes for Health Research [PJT-148746]
  2. Genome Canada Disruptive Innovations in Technology Grant [2016/7-2018/6]
  3. Natural Sciences and Engineering Research Council of Canada [RGPIN-2019-07014]
  4. Canada Research Chair Program
  5. Garron Family Cancer Centre at the Hospital for Sick Children
  6. Canada Research Chairs Program
  7. Early Researcher Award from the Ontario Ministry of Research and Innovation
  8. SickKids Restracomp Fellowship [2021/01-2021/09]
  9. CIHR CGS Graduate Scholarship [2019/09-2020/12]

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This study identifies a conserved functional role of alternative polyadenylation in oncogenic Ras function, revealing the impact of cfim-1/CFIm25 on cell migration and the previously unknown regulator mrp-5/ABCC1 through experiments in Caenorhabditis elegans and human cells.
Alternative polyadenylation of mRNA has important but poorly understood roles in development and cancer. Activating mutations in the Ras oncogene are common drivers of many human cancers. From a screen for enhancers of activated Ras (let-60) in Caenorhabditis elegans, we identified cfim-1, a subunit of the alternative polyadenylation machinery. Ablation of cfim-1 increased penetrance of the multivulva phenotype in let-60/Ras gain-of-function (gf) mutants. Depletion of the human cfim-1 ortholog CFIm25/NUDT21 in cancer cells with KRAS mutations increased their migration and stimulated an epithelial-to-mesenchymal transition. CFIm25-depleted cells and cfim-1 mutants displayed biased placement of poly(A) tails to more proximal sites in many conserved transcripts. Functional analysis of these transcripts identified the multidrug resistance protein mrp-5/ABCC1 as a previously unidentified regulator of C. elegans vulva development and cell migration in human cells through alternative 3'UTR usage. Our observations demonstrate a conserved functional role for alternative polyadenylation in oncogenic Ras function.

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