Topoisomerases and cancer chemotherapy: recent advances and unanswered questions

Area of Science:

• Molecular Biology
• Biochemistry
• Genetics

Background:

• DNA topoisomerases regulate DNA topology crucial for replication, transcription, and chromosome segregation.
• Recent studies highlight topoisomerase I (TOP1) roles in eukaryotic chromosome structure and decatenation.
• The incorporation of ribonucleotides into DNA can trap TOP1-DNA covalent complexes.

Purpose of the Study:

• To review recent advancements in understanding topoisomerase function, particularly TOP1.
• To explore the activation of DNA repair processes by trapped TOP1-DNA covalent complexes.
• To discuss novel TOP1 inhibitors and their mechanisms of action.

Main Methods:

• Literature review of studies published within the last three years.
• Analysis of research on ribonucleotide incorporation and its effect on TOP1.
• Examination of the role of nuclear proteases SPARTAN and GCNA-1 in repair pathways.

Main Results:

• Trapped TOP1-DNA covalent complexes, arising from ribonucleotide removal or drug action, activate DNA repair.
• Nuclear proteases SPARTAN and GCNA-1 are involved in these repair processes.
• New TOP1 inhibitors, including antibody-drug conjugates, function by trapping TOP1-DNA complexes.

Conclusions:

• Recent findings provide new insights into the roles of topoisomerases in maintaining genome stability.
• Trapped TOP1-DNA complexes are key mediators of DNA repair and drug-induced cytotoxicity.
• Further research is needed to fully elucidate the complexities of topoisomerase function and inhibition.