Oncotarget

Research Papers:

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

Laureen Colis _, Karita Peltonen, Paul Sirajuddin, Hester Liu, Sara Sanders, Glen Ernst, James C. Barrow and Marikki Laiho

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Oncotarget. 2014; 5:4361-4369. https://doi.org/10.18632/oncotarget.2020

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Abstract

Laureen Colis1, Karita Peltonen2, Paul Sirajuddin1, Hester Liu1, Sara Sanders3, Glen Ernst4, James C. Barrow3,4, Marikki Laiho1,2,5

1 Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

2 Center for Drug Research, University of Helsinki, 00014 Helsinki, Finland.

3 Department of Pharmacology, Johns Hopkins University, Baltimore, MD 21205, USA.

4 Lieber Institute for Brain Development, Baltimore, MD 21205, USA.

5 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Correspondence:

Marikki Laiho, email:

Keywords: DNA intercalation; small molecule; DNA damage response; transcription; RNA polymerase I; nucleolus

Received: March 27, 2014 Accepted: May 26, 2014 Published: May 26, 2014

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.


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