Topoisomerase I in Human Disease Pathogenesis and Treatments

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.

Entrapment of DNA topoisomerase-DNA complexes by nucleotide/nucleoside analogs

Topoisomerases are well-validated targets for cancer chemotherapy and DNA topoisomerase 1(Top1)is the sole target of the camptothecin(CPT)class of anticancer drugs.Over the last 20 years,multiple studies have shown Top1 activity is modulated by non-native DNA structures and this can lead to trapping of Top1 cleavage complexes(Top1cc)and conversion to DNA double strand breaks.Among the perturbations to DNA structure that generate Top1cc are nucleoside analogs that are incorporated into genomic DNA during replication including cytarabine,gemcitabine,and 5-fluoro-2’-deoxyuridine(FdU).We review the literature summarizing the role of Top1cc in mediating the DNA damaging and cytotoxic activities of nucleoside analogs.We also summarize studies demonstrating distinct differences between Top1cc induced by nucleoside analogs and CPTs,particularly with regard to DNA repair.Collectively,these studies demonstrate that,while Top1 is a common target for both Top1 poisons such as CPT and nucleoside analogs such as FdU,these agents are not redundant.In recent years,studies have shown that Top1 poisons and nucleoside analogs together with other anti-cancer drugs such as cisplatin cause replication stress and the DNA repair pathways that modulate the cytotoxic activities of these compounds are being elucidated.We present an overview of this evolving literature,which has implications for how targeting of Top1 with nucleoside analogs can be used more effectively for cancer treatment.