Topoisomerase I and Irinotecan
Topoisomerase I is an enzyme (i.e. a protein catalyzing certain biochemical reactions) which is expressed in almost every cell of the body and which is highly conserved in the phylogenetic tree. Its major function is the relaxation of DNA (desoxyribonucleic acid, the genetic material). Most DNA exists as double helix (i.e. double-stranded). The double helix is normally self-winding to achieve compact DNA which fits into the small nucleus of the cell. Under certain circumstances such as cell division an over-winding (supercoiling) of the DNA takes place. Such supercoiling of the double-stranded DNA induces torsional stress at the DNA helix bearing the risk of uncontrolled strand breaks. In order to release torsional stress from the DNA, topoisomerase I binds to the DNA and cleaves one DNA strand. This allows the rotation of the cleaved strand around the other in a controlled reaction (DNA relaxation). Afterwards, the nicked strand is re-ligated by topoisomerase I, thus restoring intact double-stranded DNA. (Figure 1) 
Topoisomerase I inhibitors stabilize a normally very transient catalytic intermediate in which topoisomerase I is bound to one strand of the DNA, known as the topoisomerase I cleavable complex. When the cleavable complex is stalled by topoisomerase I inhibitors, re-ligation of the DNA is impossible (Figure 2, left panel).
The consequences of prevented re-ligation vary; in proliferating cells the stalled topoisomerase I cleavable complex may collide with replication forks resulting in unrepairable DNA double strand breaks followed by cell death also known as apoptosis (Figure 2, right upper panel).,  For this reason, topoisomerase I inhibitors are used as anticancer drugs to treat several types of tumors.  In non-dividing cells the treatment with topoisomerase I inhibitors results in the production of single-stranded DNA breaks (Figure 2, right middle panel). Single-stranded DNA breaks are believed to reduce a cell’s replication capacity, which is not lethal. For a long time we thought that the induction of single-stranded DNA breaks might explain the effects of irinotecan on lupus nephritis. Considering the detrimental role of lupus-typical auto-antibodies against double-stranded DNA, we hypothesized that the postulated induction of DNA single strand breaks might modify the DNA in a way that impairs the binding of anti-double-stranded DNA antibodies to the DNA. Due to our hypothesis, we paid much less attention to a third effect of topoisomerase I inhibitors, that of inhibited DNA relaxation. Normally topoisomerase I binds to the DNA, induces DNA relaxation, re-ligates the DNA and moves along the DNA to the next supercoiled site. However, if a topoisomerase I inhibitor stabilizes the cleavable complex, topoisomerase I is no longer able to move along the DNA and the process of DNA relaxation is interrupted (Figure 2, right lower panel)., 
- ↑ Koiwai, O. et al. Cloning of the mouse cDNA encoding DNA topoisomerase I and chromosomal location of the gene. Gene 125, 211-6 (1993).
- ↑ Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6, 789-802 (2006).
- ↑ Hertzberg, R.P., Caranfa, M.J. & Hecht, S.M. On the mechanism of topoisomerase I inhibition by camptothecin: evidence for binding to an enzyme-DNA complex. Biochemistry 28, 4629-38 (1989).
- ↑ Bjornsti, M.A., Benedetti, P., Viglianti, G.A. & Wang, J.C. Expression of human DNA topoisomerase I in yeast cells lacking yeast DNA topoisomerase I: restoration of sensitivity of the cells to the antitumor drug camptothecin. Cancer Res 49, 6318-23 (1989).
- ↑ Hsiang, Y.H., Lihou, M.G. & Liu, L.F. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49, 5077-82 (1989).
- ↑ Rothenberg, M.L. Efficacy and toxicity of irinotecan in patients with colorectal cancer. Semin Oncol 25, 39-46 (1998).
- ↑ Hsiang, Y.H., Hertzberg, R., Hecht, S. & Liu, L.F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260, 14873-8 (1985).
- ↑ Frese, S. & Diamond, B. Structural modification of DNA-a therapeutic option in SLE? Nat Rev Rheumatol 7, 733-8 (2011).
- ↑ Champoux, J.J. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70, 369-413 (2001).
- ↑ Stewart, L., Ireton, G.C. & Champoux, J.J. A functional linker in human topoisomerase I is required for maximum sensitivity to camptothecin in a DNA relaxation assay. J Biol Chem 274, 32950-60 (1999).
- ↑ Lisby, M. et al. Residues within the N-terminal domain of human topoisomerase I play a direct role in relaxation. J Biol Chem 276, 20220-7 (2001).