Nucleic Acids Research, 2002, Vol. 30, No. 5 1198-1204
© 2002 Oxford University Press
Processing of nucleopeptides mimicking the topoisomerase I–DNA covalent complex by tyrosyl-DNA phosphodiesterase
Department of Organic Chemistry, Faculty of Chemistry, University of Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain and 1Laboratory of Molecular Pharmacology, Center for Cancer Research, Building 37, Room 5068, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA
Tyrosyl-DNA phosphodiesterase-1 (Tdp1) is the only known enzyme to remove tyrosine from complexes in which the amino acid is linked to the 3'-end of DNA fragments. 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. In the present study, we used synthetic oligodeoxynucleotide–peptide conjugates (nucleopeptides) and recombinant yeast Tdp1 to investigate the molecular determinants for Tdp1 activity. We find that Tdp1 can process nucleopeptides with up to 13 amino acid residues but is poorly active with a 70 kDa fragment of topoisomerase I covalently linked to a suicide DNA substrate. Furthermore, Tdp1 was more effective with nucleopeptides with one to four amino acids than 15 amino acids. Tdp1 was also more effective with nucleopeptides containing 15 nt than with homolog nucleopeptides containing 4 nt. These results suggest that DNA binding contributes to the activity of Tdp1 and that Tdp1 would be most effective after topoisomerase I has been proteolyzed in vivo.
* To whom correspondence should be addressed. Tel: +1 301 496 5944; Fax: +1 301 402 0752; Email: pommier{at}nih.gov Correspondence may also be addressed to Anna Grandas. Tel: +34 93 402 1263; Fax: +34 93 339 7878; Email: agrandas{at}qo.ub.es
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