Topoisomerases I & II

DNA Topoisomerases are enzymes that catalyze the unlinking of the DNA strands by making transient DNA strand breaks and allowing the DNA to rotate around these breaks.  Both Topoisomerase I (top1) and TopoisomeraseII (top2) can remove DNA supercoiling by catalyzing DNA swiveling and relaxation1

There are many top2 inhibitors and a large number of them, including the anthracyclines had been used as anticancer agents before identification of top2 as their target.  The antitumor top2 inhibitors presently used in the clinic poison the enzyme by stabilizing cleavable complexes, presumably by inhibiting DNA religation and preventing enzyme catalytic activity.   It has been found that removal of the 4-methoxy group in the newer anthracyclines such as Idarubicin exhibit greater potency against purified top2 than daunorubicin.  Anthracyclines induce mostly top2-mediated DNA double strand breaks.   

The development of a method to align and analyze DNA sequences around topoisomerase cleavage sites enabled a demonstration that drug differences were correlated with base sequence preferences and to propose the stacking model. 

Interaction of RNA transcription with cleavable complexes may play a role in the activity of top2 inhibitors.

Top2-mediated DNA damage may be responsible for the chromosomal translocations associated with etoposide-induced secondary malignancies.

1.  Y. Pommier, DNA Topoisomerases and their Inhibition by Anthracyclines, Chapter 12, pp. 183-203 in "Anthracycline Antibiotics - New Analogues, Methods of Delivery and Mechanisms of Action", Ed. W Priebe, ACS Symposium Series 574, 1995.  ISBN 0 8412 3040 4.

 

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