Phase-separated super-enhancers confer an innate radioresistance on genomic DNA.

Autor:	Matsumoto K; Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan., Ikliptikawati DK; WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan., Makiyama K; Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan., Mochizuki K; Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan., Tobita M; Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan., Kobayashi I; Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan., Voon DC; Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.; Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.; Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan., Lim K; WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan., Ogawa K; Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.; Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.; Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan., Kashiwakura I; Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan., Suzuki HI; Division of Molecular Oncology, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.; Institute for Glyco-Core Research (iGCORE), Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 464-8601, Japan.; Center for One Medicine Innovative Translational Research (COMIT), Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 464-8601, Japan., Yoshino H; Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan., Wong RW; Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.; WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.; Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.; Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan., Hazawa M; Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.; WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.; Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.; Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Jazyk:	angličtina
Zdroj:	Journal of radiation research [J Radiat Res] 2024 Jul 22; Vol. 65 (4), pp. 482-490.
DOI:	10.1093/jrr/rrae044
Abstrakt:	Recently, biomolecular condensates formed through liquid-liquid phase separation have been widely reported to regulate key intracellular processes involved in cell biology and pathogenesis. BRD4 is a nuclear protein instrumental to the establishment of phase-separated super-enhancers (SEs) to direct the transcription of important genes. We previously observed that protein droplets of BRD4 became hydrophobic as their size increase, implying an ability of SEs to limit the ionization of water molecules by irradiation. Here, we aim to establish if SEs confer radiation resistance in cancer cells. We established an in vitro DNA damage assay that measures the effect of radicals provoked by the Fenton reaction on DNA integrity. This revealed that DNA damage was markedly reduced when BRD4 underwent phase separation with DNA. Accordingly, co-focal imaging analyses revealed that SE foci and DNA damage foci are mutually exclusive in irradiated cells. Lastly, we observed that the radioresistance of cancer cells was significantly reduced when irradiation was combined with ARV-771, a BRD4 de-stabilizer. Our data revealed the existence of innately radioresistant genomic regions driven by phase separation in cancer cells. The disruption of these phase-separated components enfolding genomic DNA may represent a novel strategy to augment the effects of radiotherapy. (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)
Databáze:	MEDLINE
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