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

PDF  |  HTML  |  How to cite

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

Metrics: PDF 3226 views  |   HTML 3274 views  |   ?  


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.


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


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 2020