Topoisomerases are essential
enzymes solving
DNA topological problems such as supercoils, knots and
catenanes that arise from replication, transcription, chromatin remodeling and other
nucleic acid metabolic processes. They are also the targets of widely used anticancer drugs (e.g.
topotecan,
irinotecan, enhertu,
etoposide,
doxorubicin,
mitoxantrone) and
fluoroquinolone antibiotics (e.g.
ciprofloxacin and
levofloxacin). Topoisomerases manipulate
DNA topology by cleaving one
DNA strand (TOP1 and TOP3
enzymes) or both in concert (TOP2
enzymes) through the formation of transient
enzyme-DNA cleavage complexes (TOPcc) with phosphotyrosyl linkages between
DNA ends and the catalytic tyrosyl residue of the
enzymes. Failure in the self-resealing of TOPcc results in persistent TOPcc (which we refer it to as topoisomerase
DNA-
protein crosslinks (TOP-DPC)) that threaten genome integrity and lead to
cancers and
neurodegenerative diseases. The cell prevents the accumulation of topoisomerase-mediated DNA damage by excising TOP-DPC and ligating the associated breaks using multiple pathways conserved in eukaryotes. Tyrosyl-
DNA phosphodiesterases (TDP1 and TDP2) cleave the tyrosyl-
DNA bonds whereas structure-specific
endonucleases such as Mre11 and XPF (Rad1) incise the
DNA phosphodiester backbone to remove the TOP-DPC along with the adjacent
DNA segment. The
proteasome and
metalloproteases of the WSS1/Spartan family typify proteolytic repair pathways that debulk TOP-DPC to make the
peptide-
DNA bonds accessible to the TDPs and
endonucleases. The purpose of this review is to summarize our current understanding of how the cell excises TOP-DPC and why, when and where the cell recruits one specific mechanism for repairing topoisomerase-mediated DNA damage, acquiring resistance to therapeutic
topoisomerase inhibitors and avoiding
genomic instability,
cancers and
neurodegenerative diseases.