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Jan 17, 2008

Transcriptional Complex Associated with Cancer and Normal Stem Cell Gene Expression

  • Two new studies, published in the January 18 issue of Molecular Cell, reportedly link the recently discovered function of a multifaceted transcriptional complex to control of gene expression in both normal cells and cancer stem cells.

    Initiation of transcription requires sophisticated coordination of many different regulatory factors. Coactivators are multisubunit complexes that facilitate transcription initiation directly by interacting with RNA polymerase and general transcription factors or indirectly by influencing chromatin.

    The yeast SAGA complex and the homologue metazoan TFTC/STAGA, or hSAGA, are HAT-containing complexes that facilitate access of general transcriptional factors to DNA through histone acetylation. Although hSAGA is thought to be a homologue of the well-studied yeast SAGA complex, its subunit composition and functions are not as well understood.

    Researchers in the first study identified three novel subunits—ATXN7L3, USP22, and ENY2—that are homologues of previously described subunits in the yeast SAGA complex. They demonstrated that the newly identified subunits work together to remove the ubiquitin moiety from monoubiquitylated histone H2B. This is similar to what has been previously described in yeast. They also found that the subunits remove the ubiquitin moiety from monoubiquitylated histone H2A. The latter modification is not found in yeast but is more prevalent than monoubiquitylated H2B in mammals.

    Importantly, the deubiquitylation module of the Drosophila TFTC/STAGA complex was an enhancer of position effect variegation and counteracted heterochromatin silencing. Additionally, both the Drosophila and the human deubiquitylation module were shown to be required for full transcriptional activation by the androgen receptor, which is often deregulated in prostate cancer.

    Working in parallel, a second research group from the Kimmel Cancer Center also identified USP22 as a member of hSAGA. Previous work had identified USP22 as part of an 11 gene cancer stem cell signature that accurately distinguished patients whose tumors would eventually metastasize from those whose tumors would remain localized.

    The researchers demonstrated that USP22 is required for activation of target gene transcription by the MYC oncoprotein and that USP22 depletion compromises MYC functions (including transformation of mammalian cells) and leads to cell cycle arrest.

    The first study was conducted by researchers at the Universite´ Louis Pasteur de Strasbourg, the University of Tokyo, Universitat Freiburg, Radboud University, and the Russian Academy of Sciences. Besides researchers at the Kimmel Cancer Center, the second study was conducted by scientists at the University of Pennsylvania School of Medicine, University of Portsmouth, and the Wistar Institute.



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