Portal de Periódicos da CAPES

A Targeting Modality for Destruction of RNA Polymerase I that Possesses Anticancer Activity

2014; Cell Press; Volume: 25; Issue: 1 Linguagem: Inglês

10.1016/j.ccr.2013.12.009

1878-3686

Karita Peltonen, Laureen Colis, Hester Liu, Rishi Trivedi, Michael S. Moubarek, Henna M. Moore, Baoyan Bai, Michelle A. Rudek, Charles J. Bieberich, Marikki Laiho,

Genomics and Chromatin Dynamics

We define the activity and mechanisms of action of a small molecule lead compound for cancer targeting. We show that the compound, BMH-21, has wide and potent antitumorigenic activity across NCI60 cancer cell lines and represses tumor growth in vivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polymerase I (Pol I) transcription. Strikingly, we find that BMH-21 causes proteasome-dependent destruction of RPA194, the large catalytic subunit protein of Pol I holocomplex, and this correlates with cancer cell killing. Our results show that Pol I activity is under proteasome-mediated control, which reveals an unexpected therapeutic opportunity.