Abstract
DNA topoisomerases are enzymes that catalyze changes in the torsional and flexural strain of DNA molecules. Earlier studies implicated these enzymes in a variety of processes in both prokaryotes and eukaryotes, including DNA replication, transcription, recombination, and chromosome segregation. Studies performed over the past 3 years have provided new insight into the roles of various topoisomerases in maintaining eukaryotic chromosome structure and facilitating the decatenation of daughter chromosomes at cell division. In addition, recent studies have demonstrated that the incorporation of ribonucleotides into DNA results in trapping of topoisomerase I (TOP1)–DNA covalent complexes during aborted ribonucleotide removal. Importantly, such trapped TOP1–DNA covalent complexes, formed either during ribonucleotide removal or as a consequence of drug action, activate several repair processes, including processes involving the recently described nuclear proteases SPARTAN and GCNA-1. A variety of new TOP1 inhibitors and formulations, including antibody–drug conjugates and PEGylated complexes, exert their anticancer effects by also trapping these TOP1–DNA covalent complexes. Here we review recent developments and identify further questions raised by these new findings.
Highlights
The helical structure of duplex DNA provides a physical basis for the faithful duplication and deciphering of genetic information while ensuring DNA strand integrity
Further studies attribute this olaparib hypersensitivity to increased ribonucleotide-dependent stabilization of TOP1ccs, which can serve as PARP1 substrates
TOP1MT physically associates with mitochondrial ribosome subunits to promote mitochondrial translation, which is critical for hepatocellular carcinoma cell growth[24]. These findings suggest that inhibition of TOP1MT activity, rather than stabilization of TOP1MTccs, might be an effective strategy for targeting this enzyme to treat some cancers
Summary
The helical structure of duplex DNA provides a physical basis for the faithful duplication and deciphering of genetic information while ensuring DNA strand integrity. A recent genome-wide CRISPR screen showed that interruption of genes encoding the three subunits of RNase H2 enhances human cell line sensitivity to the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib[22] Further studies attribute this olaparib hypersensitivity to increased ribonucleotide-dependent stabilization of TOP1ccs, which can serve as PARP1 substrates. These observations have been translated into protracted schedules of both irinotecan[111] and etoposide[112] Because these prolonged schedules can be inconvenient and toxic[111], there has been an ongoing search for alternatives, including new topoisomerase poisons, drug formulations that extend the half-life of TOPccs, and strategies to increase tumor-selective drug delivery (Table 3)[113]. Targets HER2-expressing tumors with activity against low-expressing tumor cells[123,124]
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