Tyrosyl-DNA Phosphodiesterase Mechanisms in DNA Damage Repair

Tyrosyl-DNA phosphodiesterases (TDPs) are specialised enzymes that resolve covalent complexes formed between topoisomerases and DNA during normal cellular processes and in response to genotoxic stress. In particular, TDP1 hydrolyses the 3′-phosphotyrosyl bond linking DNA to the catalytic tyrosine of topoisomerase I, thereby initiating repair of both abortive single-strand breaks and secondary double-strand breaks that arise during transcription and replication. A parallel pathway, mediated by TDP2, addresses 5′-phosphotyrosyl linkages generated by topoisomerase II. These activities are integrated with core DNA repair pathways—base excision repair, homologous recombination and non-homologous end-joining—to maintain genomic integrity. Beyond basic enzymology, recent work has illuminated the regulation of TDP1 by post-translational modifications, its interplay with accessory repair factors and the therapeutic potential of small-molecule inhibitors to sensitise tumour cells to topoisomerase poisons. Collectively, these advances underscore the global significance of TDP-mediated repair in preventing chromosomal translocations, preserving transcriptional fidelity and shaping responses to anticancer and antiviral agents.

Research from Nature Portfolio

Recent studies have detailed how TDP1 safeguards genome stability by preventing erroneous repair of transcription-associated breaks. One investigation demonstrated that, in human cells, TDP1 suppresses chromosomal translocations and cell death arising from abortive topoisomerase I activity during gene transcription. The work uncovered an error-prone end-joining pathway involving the MRN complex that is normally restrained by TDP1, emphasising its role in both single-strand break resolution and the prevention of double-strand break–induced genome rearrangements. A complementary chemical biology study reported the first successful application of sulphur(VI) fluoride exchange (SuFEx) chemistry to engineer covalent ligands targeting a tyrosine residue within the shallow catalytic pocket of TDP1. By demonstrating site-specific modification of Y204, this work not only advances inhibitor design but also provides a versatile toolkit for probing TDP1 dynamics in live cells.

Tyrosyl-DNA Phosphodiesterase Mechanisms in DNA Damage Repair publication trend

The graph below shows the total number of articles in tyrosyl-dna phosphodiesterase mechanisms in dna damage repair across all publications each year (not limited to Nature Index journals).

Technical terms

Tyrosyl-DNA phosphodiesterase (TDP): Enzyme that cleaves covalent bonds between a DNA terminus and a tyrosine residue of a trapped topoisomerase.

Topoisomerase I cleavage complex (Top1cc): Transient intermediate in which topoisomerase I is covalently linked to DNA, resolved by TDP1.

Single-strand break (SSB): A discontinuity in one strand of the DNA duplex that must be repaired to prevent secondary lesions.

Double-strand break (DSB): A break affecting both DNA strands, often more deleterious and repaired by non-homologous end-joining or homologous recombination.

Non-homologous end-joining (NHEJ): A repair pathway that directly ligates broken DNA ends without the need for a homologous template.

Sulphur(VI) fluoride exchange (SuFEx): A click-chemistry reaction enabling selective covalent modification of protein residues for ligand design.

References

1. TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription. Nature Communications (2023).
2. Oxidative DNA damage and repair at non-coding regulatory regions. Trends in Cell Biology (2023).
3. TDP1 phosphorylation by CDK1 in mitosis promotes MUS81-dependent repair of trapped Top1-DNA covalent complexes. The EMBO Journal (2024).
4. Targeted sulfur(VI) fluoride exchange-mediated covalent modification of a tyrosine residue in the catalytic pocket of tyrosyl-DNA phosphodiesterase 1. Communications Chemistry (2024).
5. Natural Products and Their Derivatives as Inhibitors of the DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1. International Journal of Molecular Sciences (2023).