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Details

Autor(en) / Beteiligte
Titel
BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer
Ist Teil von
  • Cell reports (Cambridge), 2018-01, Vol.22 (3), p.796-808
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2018
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
  • BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy. [Display omitted] •BRD4 promotes NHEJ DNA repair and regulates the expression of DNA repair genes•BRD4 mediates the formation of TMPRSS2-ERG gene fusions in prostate cancer•DNA-damage-induced histone H4 acetylation recruits BRD4 to chromatin•BRD4 expression is associated with the development of CRPC after radiation therapy The classic function of BRD4 is to regulate gene expression. Li et al. present experimental and clinical data to suggest that BRD4 is also a key player in DNA repair and is associated with the development of CRPC after radiation therapy.

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