4.5 Article

G-quadruplexes Sequester Free Heme in Living Cells

Journal

CELL CHEMICAL BIOLOGY
Volume 26, Issue 12, Pages 1681-+

Publisher

CELL PRESS
DOI: 10.1016/j.chembiol.2019.10.003

Keywords

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Funding

  1. US NIH National Cancer Institute [P01CA077852]
  2. Agence Nationale de la Recherche [ANR 14-CE35-0003-02]
  3. PIC3i program from Institut Curie [91730]
  4. French Ministry of Education, Research and Technology
  5. Agence Nationale de la Recherche (ANR) [ANR-14-CE35-0003] Funding Source: Agence Nationale de la Recherche (ANR)

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Heme is an essential cofactor for many enzymes, but free heme is toxic and its levels are tightly regulated. G-quadruplexes bind heme avidly in vitro, raising the possibility that they may sequester heme in vivo. If so, then treatment that displaces heme from quadruplexes is predicted to induce expression of genes involved in iron and heme homeostasis. Here we show that PhenDC3, a G-quadruplex ligand structurally unrelated to heme, displaces quadruplex-bound heme in vitro and alters transcription in cultured human cells, upregulating genes that support heme degradation and iron homeostasis, and most strikingly causing a 30-fold induction of heme oxidase 1, the key enzyme in heme degradation. We propose that G-quadruplexes sequester heme to protect cells from the pathophysiological consequences of free heme.

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