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Compensatory RNA polymerase 2 loading determines the efficacy and transcriptional selectivity of JQ1 in Myc-driven tumors

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اقرأ أكثر حفظ في قائمتي
  • نوع التسجيلة:
    Electronic Resource
  • الدخول الالكتروني :
    https://hdl.handle.net/10281/446761
    http://www.nature.com/doifinder/10.1038/leu.2016.182
    info:eu-repo/semantics/altIdentifier/pmid/27443262
    info:eu-repo/semantics/altIdentifier/wos/WOS:000394058800023
    volume:31
    issue:2
    firstpage:479
    lastpage:490
    numberofpages:12
    journal:LEUKEMIA
  • معلومة اضافية
    • Publisher Information:
      Nature Publishing Group country:GB 2017
    • Added Details:
      Donato, E
      Croci, O
      Sabò, A
      Muller, H
      Morelli, M
      Pelizzola, M
      Campaner, S
      Donato E
      Croci O
      Sabò A
      Muller H
      Morelli MJ
      Pelizzola M
      Campaner S
    • نبذة مختصرة :
      Inhibition of bromodomain and extraterminal motif (BET) proteins such as BRD4 bears great promise for cancer treatment and its efficacy has been frequently attributed to Myc downregulation. Here, we use B-cell tumors as a model to address the mechanism of action of JQ1, a widely used BET inhibitor. Although JQ1 led to widespread eviction of BRD4 from chromatin, its effect on gene transcription was limited to a restricted set of genes. This was unlinked to Myc downregulation or its chromatin association. Yet, JQ1-sensitive genes were enriched for Myc and E2F targets, were expressed at high levels, and showed high promoter occupancy by RNAPol2, BRD4, Myc and E2F. Their marked decrease in transcriptional elongation upon JQ1 treatment, indicated that BRD4-dependent promoter clearance was rate limiting for transcription. At JQ1-insensitive genes the drop in transcriptional elongation still occurred, but was compensated by enhanced RNAPol2 recruitment. Similar results were obtained with other inhibitors of transcriptional elongation. Thus, the selective transcriptional effects following JQ1 treatment are linked to the inability of JQ1-sensitive genes to sustain compensatory RNAPol2 recruitment to promoters. These observations highlight the role of BET proteins in supporting transcriptional elongation and rationalize how a general suppression of elongation may selectively affects transcription.
    • الموضوع:
      MYC, BRD4, BET inhibitor, JQ1, RNA polymerase II, B-cell tumor; BIO/11 - BIOLOGIA MOLECOLARE; info:eu-repo/semantics/article
    • Note:
      STAMPA
      English
    • Other Numbers:
      ITBAO oai:boa.unimib.it:10281/446761
      10.1038/leu.2016.182
      info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84979300705
      1415733341
    • Contributing Source:
      BICOCCA OPEN ARCH
      From OAIster®, provided by the OCLC Cooperative.
    • الرقم المعرف:
      edsoai.on1415733341
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