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Topoisomerase I in Human Disease Pathogenesis and Treatments
1Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA 91010-3000, USA.
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.
Insights
Mammalian topoisomerase 1 (TOP1) is crucial for DNA replication and transcription. Its dual role in maintaining DNA topology and causing DNA damage makes it a target for cancer therapies and potential treatments for autism spectrum disorders.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Mammalian topoisomerase 1 (TOP1) is essential for DNA replication and transcription by relaxing supercoiled DNA.
- TOP1 activity can lead to toxic DNA damage through TOP1-DNA covalent trapping, impacting cell growth and genome stability.
- This dual role presents a paradox: TOP1 is vital for cell function yet can induce harmful lesions.
Purpose of the Study:
- To review the multifaceted roles of TOP1 in human health and disease.
- To explore how TOP1 activity contributes to tumorigenesis and developmental disorders.
- To summarize current strategies targeting TOP1 for therapeutic interventions.
Main Methods:
- Literature review of studies on TOP1 function, DNA damage, and therapeutic applications.
- Analysis of the mechanisms underlying TOP1-induced DNA lesions.
- Examination of TOP1's role in cancer and neurological disorders.
Main Results:
- TOP1's essential catalytic activity is balanced against its potential to cause genotoxicity.
- TOP1-induced DNA lesions are exploited in cancer chemotherapy.
- Emerging evidence implicates TOP1 in transcriptional regulation relevant to autism spectrum disorders.
Conclusions:
- TOP1 plays a critical, complex role in human health, influencing DNA topology, genome stability, and gene expression.
- Targeting TOP1 offers therapeutic opportunities for cancer and potentially for specific subtypes of autism.
- Further research is needed to fully elucidate TOP1's functions and optimize its therapeutic targeting.
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