Disease relevance of TDP1

• We found that deletion of the TDP1 gene in yeast confers hypersensitivity to Top2 targeting agents [1].
• Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy [2].

High impact information on TDP1

• The His493 residue is conserved in TDP1 across species and is located in the active site of the enzyme [2].
• Using genome-wide linkage mapping and a positional candidate approach in a Saudi Arabian family affected with autosomal recessive SCAN1, we identified a homozygous mutation in TDP1 (A1478G) that results in the substitution of histidine 493 with an arginine residue [2].
• We propose that loss-of-function mutations in TDP1 may cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in postmitotic neurons [2].
• Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs covalently bound topoisomerase I-DNA complexes and is essential for preventing the formation of double-strand breaks that result when stalled topoisomerase I complexes interfere with DNA replication in yeast [2].
• Our results show that Tdp1 plays more general roles in DNA repair than repair of Top1 mediated DNA damage, and may participate in repairing many types of base damage to DNA [1].

Biological context of TDP1

• The role of TDP1 from budding yeast in the repair of DNA damage [3].
• However, the value of TDP1 in the economy of the cell is highlighted by our discovery of several phenotypes that are evident even without deliberate inactivation of parallel pathways [3].
• In this work we engineered a point mutation in TDP1 and present evidence that, as per design, it severely diminishes tyrosyl-DNA phosphodiesterase enzyme activity without affecting protein folding [3].
• RESULTS: Reaction kinetics with model substrates reveal that the catalytic efficiency of Saccharomyces cerevisiae Tdp1 is relatively poor when the scissile bond is located in the middle of a duplex, but much better when it is located at the end of a structure [4].
• Such complexes can be produced following DNA processing by topoisomerase I, and recent studies in yeast have demonstrated the importance of TDP1 for cell survival following topoisomerase I-mediated DNA damage [5].

Associations of TDP1 with chemical compounds

• The source of these phosphates remains enigmatic, however, because apn1 tpp1 rad1 slow growth could be correlated with neither the presence of a yeast delta-lyase, the activity of the 3'-phosphate-generating enzyme Tdp1, nor levels of endogenous oxidation [6].
• The phenotypes of yeast strains that express this mutant show that the contribution of TDP1 to the repair of two kinds of damaged termini-induced, respectively, by camptothecin (CPT) and by bleomycin-strongly depends on enzyme activity [3].
• Recombinant hTdp1, as well as Saccharomyces cerevisiae Tdp1, catalyzed similar removal of glycolate, although less efficiently than removal of tyrosine [7].
• Fractionated human whole-cell extracts contained an activity, which in the presence of EDTA, catalyzed removal of glycolate from phosphoglycolate at a single-stranded 3' terminus to leave a 3'-phosphate, reminiscent of the human tyrosyl-DNA phosphodiesterase hTdp1 [7].
• Tyrosyl-DNA phosphodiesterase (TDP) cleaves the phosphodiester bond linking the active site tyrosine residue of topoisomerase I with the 3' terminus of DNA in topoisomerase I-DNA complexes which accumulate during treatment of cancer with camptothecin [8].

Other interactions of TDP1

• Thus, tdp1 rad1 cells (including the catalytic point mutant rad1-D869A) not only are highly sensitive to the Top1 poison camptothecin but also exhibit a TOP1-dependent growth delay [9].
• In the absence of RAD9, inactivation of TDP1 has a significant effect on the survival of cells following exposure to camptothecin but is without consequence for the survival of agents that do not target topoisomerase I. CONCLUSIONS: Tdp1 acts as a specific repair enzyme for topoisomerase I lesions [4].

References