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Transcription-coupled cellular stress is associated with several physiological and pathological features, including membraneless biomolecular condensates. In the study by Yasuhara et al., the authors have described specific nuclear condensates in multiple cell types upon inhibition of RNA polymerase II transcription, discovered their main constituent proteins, and elucidated their functions. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer., Competing Interests: of Potential Conflicts of Interest: A.M.C. is a co-inventor on a patent filed by the University of Michigan covering the diagnostic and therapeutic field of use for ETS fusions in prostate cancer. The diagnostic field of use has been licensed to Hologic. Hologic did not play a role in the design and conduct of this study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the article., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)