title: DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response.
abstract: DNA intercalation is a major therapeutic modality for cancer therapeutic drugs. The therapeutic activity comes at a cost of normal tissue toxicity and genotoxicity. We have recently described a planar heterocyclic small molecule DNA intercalator, BMH-21, that binds ribosomal DNA and inhibits RNA polymerase I (Pol I) transcription. Despite DNA intercalation, BMH-21 does not cause phosphorylation of H2AX, a key biomarker activated in DNA damage stress. Here we assessed whether BMH-21 activity towards expression and localization of Pol I marker proteins depends on DNA damage signaling and repair pathways. We show that BMH-21 effects on the nucleolar stress response were independent of major DNA damage associated PI3-kinase pathways, ATM, ATR and DNA-PKcs. However, testing a series of BMH-21 derivatives with alterations in its N,N-dimethylaminocarboxamide arm showed that several derivatives had acquired the property to activate ATM- and DNA-PKcs -dependent damage sensing and repair pathways while their ability to cause nucleolar stress and affect cell viability was greatly reduced. The data show that BMH-21 is a chemically unique DNA intercalator that has high bioactivity towards Pol I inhibition without activation or dependence of DNA damage stress. The findings also show that interference with DNA and DNA metabolic processes can be exploited therapeutically without causing DNA damage.
authors: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Laureen
authors: L
authors: Colis
authors: Karita
authors: K
authors: Peltonen
authors: Paul
authors: P
authors: Sirajuddin
authors: Hester
authors: H
authors: Liu
authors: Sara
authors: S
authors: Sanders
authors: Glen
authors: G
authors: Ernst
authors: James C
authors: JC
authors: Barrow
authors: Center for Drug Research, University of Helsinki, 00014 Helsinki, Finland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Marikki
authors: M
authors: Laiho
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D006801:Humans; D007364:Intercalating Agents; D008958:Models, Molecular; D010766:Phosphorylation; D012318:RNA Polymerase I; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D007364:Intercalating Agents; D025521:Tumor Suppressor Proteins; D012318:RNA Polymerase I