TOP1

Case Study 1: Andreas Keil, 2016

Since the precise mechanism for the pathogenesis of systemic lupus erythematosus (SLE) is unknown, no targeted therapies in addition to immunosuppression are available so far. The researchers recently demonstrated that administration of the topoisomerase I (topo I) inhibitor irinotecan at extremely low concentrations reversed established lupus nephritis in NZB/NZW mice. While profound immunosuppression was absent, we proposed changes in DNA relaxation and anti-double-stranded (ds)DNA antibody binding as the underlying mechanism. To exclude that these effects were restricted to NZB/NZW mice, irinotecan was used in a genetically different strain of lupus-prone mice.

MRL/lpr mice were treated with high- and low-dose irinotecan beginning at 8 weeks of age. Treatment was repeated every fourth week. In vitro, DNA was relaxed by recombinant topo I, and altered anti-dsDNA antibody binding was measured by enzyme-linked immunosorbent assay. Administration of both high- and low-dose irinotecan prevented proteinuria and prolonged survival in MRL/lpr mice. Moreover, both concentrations of irinotecan significantly improved histopathology of the skin at 18 weeks of age. While only high-dose irinotecan diminished the numbers of plasmablasts and double-negative T cells, no changes in IgG-secreting cells or anti-dsDNA IgG were observed.

Fig1. Frequency of proteinuria measured as grade 4+ at two consecutive weeks.

Fig2. Increased binding of anti-double-stranded DNS (dsDNA) IgG but not of anti-dsDNA IgM to DNA treated with topoisomerase I (topo I).

Case Study 2: Andreas Keil, 2015

The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. While irinotecan is known to stabilize the complex of topo I and DNA, the enzyme tyrosyl-DNA phosphodiesterase 1 (TDP-1) functions in an opposing manner by releasing topo I from DNA. Therefore, we undertook this study to test whether the TDP-1 inhibitor furamidine has an additional effect on lupus nephritis when used in combination with irinotecan.

NZB/NZW mice were treated with low-dose irinotecan and furamidine either alone or in combination beginning at age 26 weeks. DNA relaxation was visualized using gel electrophoresis. Binding of anti-double-stranded DNA (anti-dsDNA) antibodies to DNA modified by topo I, TDP-1, and the topo I inhibitor camptothecin was determined by enzyme-linked immunosorbent assay. In vitro, recombinant TDP-1 increased topo I-mediated DNA relaxation, resulting in enhanced binding of anti-dsDNA antibodies. In combination with topo I and camptothecin, TDP-1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti-dsDNA binding.

Fig3. Supercoiled plasmid DNA pBR322 (50 g/ml) was incubated with 30 ng/ml topo I and 7.25 mg/ml TDP-1 or bovine serum albumin (BSA) for 15, 30, or 60 minutes at 37°C.

Fig4. Effect of camptothecin on anti-dsDNA binding.

Fig1. TOP1-DPC arrest the replication forks upon their collision and signal the DCAF13-DDB1-CUL4-RBX1 complex for its recruitment to the DPCs. (Yilun Sun, 2023)

Fig2. Model for the molecular mechanism by which THZ1 enhances TPT-mediated cytotoxicity in SCLC cells. (Yilun Sun, 2022)

TOP1 involved in several pathways and played different roles in them. We selected most pathways TOP1 participated on our site, such as Caspase cascade in apoptosis, Integrated Pancreatic Cancer Pathway, which may be useful for your reference. Also, other proteins which involved in the same pathway with TOP1 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

TOP1 has several biochemical functions, for example, DNA binding, DNA topoisomerase type I activity, DNA topoisomerase type II (ATP-hydrolyzing) activity. Some of the functions are cooperated with other proteins, some of the functions could acted by TOP1 itself. We selected most functions TOP1 had, and list some proteins which have the same functions with TOP1. You can find most of the proteins on our site.

TOP1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with TOP1 here. Most of them are supplied by our site. Hope this information will be useful for your research of TOP1.

lt_sv40; NKX3-1; ABL1