Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 19, Issue 11, Pages 1139-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2390
Keywords
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Funding
- Institut National du Cancer [2008-1-PL BIO 01]
- Agence Nationale de la Recherche [BLAN07-3_186592]
- Association d'Aide a la Recherche Cancerologique de Saint-Cloud
- Fondation Recherche Medicale [Equipe FRM DEQ20110421278]
- Association pour la Recherche sur le Cancer
- FRM
- Ligue Nationale Contre le Cancer
- Association Francaise contre les Myopathies
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Both epigenetic and splicing regulation contribute to tumor progression, but the potential links between these two levels of gene-expression regulation in pathogenesis are not well understood. Here, we report that the mouse and human RNA helicases Ddx17 and Ddx5 contribute to tumor-cell invasiveness by regulating alternative splicing of several DNA-and chromatin-binding factors, including the macroH2A1 histone. We show that macroH2A1 splicing isoforms differentially regulate the transcription of a set of genes involved in redox metabolism. In particular, the SOD3 gene that encodes the extracellular superoxide dismutase and plays a part in cell migration is regulated in an opposite manner by macroH2A1 splicing isoforms. These findings reveal a new regulatory pathway in which splicing factors control the expression of histone variant isoforms that in turn drive a transcription program to switch tumor cells to an invasive phenotype.
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