Dysregulation of gene expression is hallmark of cancer. Effective cancer treatment to regulate gene expression, is limited by off-target effects of many DNA binding drugs. Since DNA motif targetted by the drugs are repeated multiple times in the genome hence the drug also ends up binding at multiple locations resulting in many undesired effects. To restore normal expression of a cancer gene, it is imperative that the drug binds in a gene specifc manner. Our hypothesis is that core binding motif of a Transcription Factor may be repeated many a times in the genome, but not the neighbouring sequences. Hence, our drug designing approach is to target the core DNA motif as anchor and extend it into the adjoining sequences (upstream, downstream or on both sides of the core motif) to make it unique. Thus, an effective drug will specifically bind this extended sequence in the gene. e.g. If a Transcription Factor regulates 10 genes then we should be able to design 10 different drugs which will uniquely target binding of this TF in a gene specific manner without any overlap.

This requires a knowledge of (i) genes implicated in cancer, (ii) functional regulatory motifs in all such genes, and (iii) a tool to predict unique sequence for all such regulatory motifs in each of these cancer causing genes.

Towards this, we created (i) a database of functional regulatory motifs in 937 cancer causing genes and (ii) developed a software USP (Unique Sequence Predictor) to predict unique target motifs for drug binding in a gene specific manner. Both these features are conbined into a single platform which we call Onco-Regulon.

 

 

Related Publications

  • B. Jayaram, Tanya Singh, Marcia Fenley, "DNA-Drug Interactions: A Theoretical Perspective" in "Methods for Studying DNA/Drug Interactions", Editors, Dr. Meni Wanunu & Prof. Yitzhak Tor, 2011,Ch-14, 317-338, CRC Press.

  • Prateek Pandya, Surendra P. Gupta, Kumud Pandav, Ritu Barthwal, B. Jayaram and Surat Kumar, "DNA Binding Studies of Vinca Alkaloids: Experimental and Computational Evidence", NPC Natural Product Communications, 2012 Vol. 7(3),  305-309.

  • M. O. Fenley, R. Harris, B. Jayaram, A. H. Boschitsch, "Revisiting the association of cationic groove-binding drugs to DNA using a poisson-boltzmann approach", Biophys J., 2010, 99(3), 879-886.