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Sadeq Vallian

University of Isfahan, Iran

Title: Genome variation and drug resistance: Effects of non-synonymous polymorphisms on Topoisomerase II α (Top2-α) drug interaction


Sadeq Vallian finished his PhD degree at King’s College London, London in 1996. Then he did his post-doctoral fellowship in Laboratory Medicine at M.D. Anderson Cancer Center, Texas University, Texas in 1999. He then moved to University of Isfahan, Isfahan, IR Iran, and started his independent research work as an assistant professor in 2000. Now he is a full-time professor in the department of biology, at University of Isfahan. His research was mainly focused on human genome variation and genetic diseases and cancer. In the last two years, two projects have been running in his lab, i) the effects of genomic variation and non-synonymous polymorphisms in drug/target interactions in cancer chemotherapy especially those affecting Topoisomerase II and its targeting drugs; ii) Genomic polymorphism and non-coding RNA, their expression and target interactions. 


Topoisomerases are the key enzymes involved in resolving the winding of DNA during DNA replication, transcription, recombination, and chromatin remodeling. Because of the essential roles of these enzymes in the maintenance of genome stability and cell function, topoisomerases were the important targets for cancer chemotherapy drugs. To date, several topoisomerase inhibitors have been introduced and applied as drugs in the treatment of cancer. Topoisomerase II α (Top2-α), a subclass of topoisomerase II enzymes, functions as an important target for several anticancer drugs. It seems that genomic variations such as non-synonymous polymorphisms (nsSNP) could affect the enzyme/drug interactions. Our main focus has been the study of the mechanisms by which non-synonymous genomic variations in Top2-α could affect its interaction with anticancer drugs such as Amsacrine and Mitoxantrone as important inhibitors of the enzyme. In the first step we identified the main residues involved in the interaction between the enzyme and the drugs. In <5°A space around the drug, the main residues were Lys489, Asn504, Glu506, Arg487 and Ile490 for Mitoxantrone, and for Amsacrine, the interaction was through Glu506, Leu491, Arg487, Gly488, Lys489, Ile490 and Asn504 residues. Next, the effects of non-synonymous polymorphisms (nsSNPs) were examined on the interaction of Top2-α with the drugs. The results showed that variants K529E, R568H, R568G, T530M and R487K, Y481C could affect the inhibition by Amsacrine and Mitoxantrone, respectively. This suggested that nsSNPs could clearly affect the inhibition of Top2-α causing possible drug-resistant. These results could facilitate the prediction and development of drugs for specific Top2-α inhibition, making the cancer chemotherapy more effective.