DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response

Oncotarget. 2014 Jun 30;5(12):4361-9. doi: 10.18632/oncotarget.2020.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics*
  • DNA Damage / genetics*
  • Humans
  • Intercalating Agents
  • Models, Molecular
  • Phosphorylation
  • RNA Polymerase I
  • Signal Transduction
  • Tumor Suppressor Proteins / genetics*

Substances

  • Cell Cycle Proteins
  • Intercalating Agents
  • Tumor Suppressor Proteins
  • RNA Polymerase I