Topoisomerase I in Human Disease Pathogenesis and Treatments

Abstract

Mammalian topoisomerase 1 (TOP1) is an essential enzyme for normal development. TOP1 relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and transcription and thus block cell growth. Unfortunately, this exact activity can covalently trap TOP1 on the DNA that could lead to cell death or mutagenesis, a precursor for tumorigenesis. It is therefore important for cells to find a proper balance between the utilization of the TOP1 catalytic activity to maintain DNA topology and the risk of accumulating the toxic DNA damages due to TOP1 trapping that prevents normal cell growth. In an apparent contradiction to the negative attribute of the TOP1 activity to genome stability, the detrimental effect of the TOP1-induced DNA lesions on cell survival has made this enzyme a prime target for cancer therapies to kill fast-growing cancer cells. In addition, cumulative evidence supports a direct role of TOP1 in promoting transcriptional progression independent of its topoisomerase activity. The involvement of TOP1 in transcriptional regulation has recently become a focus in developing potential new treatments for a subtype of autism spectrum disorders. Clearly, the impact of TOP1 on human health is multifold. In this review, we will summarize our current understandings on how TOP1 contributes to human diseases and how its activity is targeted for disease treatments.

(S)-10-Hydroxycamptothecin Inhibits Esophageal Squamous Cell Carcinoma Growth In Vitro and In Vivo Via Decreasing Topoisomerase I Enzyme Activity

“…Accumulating data indicated that HCPT formed a complex with DNA and TOP I, resulting in double strand DNA breakage and cell death directly [15,32]. Since human TOP I is essential for topological stress releasing and topology modulation, the damage of TOP I function will lead to supercoiled DNA because the DNA strands cannot release superhelix during transcription and replication [4]. Thus, the amount of supercoiled DNA will reflect the enzyme activity of TOP I in double strand DNA superhelix locally unwinding.…”

“…Topoisomerase I (TOP I) is an essential enzyme in both prokaryotes and eukaryotes [4]. TOP I is involved in the process of supercoiled DNA relaxation and the alleviation of the DNA helical constraints [5].…”

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

“…Topoisomerase 1 (Top1) creates transient single-DNA nicks, while topoisomerases 2 (Top2α and Top2β) produce transient double-stranded DNA breaks. Both nuclear Top1 and Top2 are important targets for cancer chemotherapy, and Top inhibitors are used in therapeutic protocols [ 65 , 66 , 67 ]. Top inhibitors are classified into two groups: poisons and catalytic inhibitors.…”

MicroRNA‑139 suppresses hepatocellular carcinoma cell proliferation and migration by directly targeting Topoisomerase I

“…Furthermore, it has been determined that TOP1 is highly expressed in a number of malignancy types, including colon cancer and breast cancer (35,36), indicating its potential role in tumorigenesis. The major effect of TOP1-induced DNA lesions on cell survival has resulted in this enzyme being a prime target for cancer therapies to kill fast-growing cancer cells (37). To date, a number of TOP1 inhibitors have been developed, including camptothecins, irinotecan and topotecan.…”