title: Tyrosyl-DNA phosphodiesterase I resolves both naturally and chemically induced DNA adducts and its potential as a therapeutic target.
abstract: DNA is subject to a wide range of insults, resulting from endogenous and exogenous sources that need to be metabolized/resolved to maintain genome integrity. Tyrosyl-DNA phosphodiesterase I (Tdp1) is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts. As a phospholipase D superfamily member Tdp1 utilizes two catalytic histidines each within a His-Lys-Asn motif. Tdp1 was discovered for its ability to hydrolyze the 3'-phospho-tyrosyl that in the cell covalently links DNA Topoisomerase I (Topo1) and DNA. Tdp1's list of substrates has since grown and can be divided into two groups: protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogs. Since many of Tdp1's substrates are generated by clinically relevant chemotherapeutics, Tdp1 became a therapeutic target for molecularly targeted small molecules. Tdp1's unique catalytic cycle allows for two different targeting strategies: (1) the intuitive inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of chemotherapeutically induced DNA adducts, thereby enhancing their toxicity and (2) stabilization of the Tdp1-DNA covalent reaction intermediate, prevents resolution of Tdp1-DNA adduct and increases the half-life of this potentially toxic DNA adduct. This concept is best illustrated by a catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy, and results in an increased stability of its Tdp1-DNA reaction intermediate. Here, we will discuss Tdp1 catalysis from a structure-function perspective, Tdp1 substrates and Tdp1 potential as a therapeutic target.
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham , Birmingham, AL , USA.
authors.forename: Evan Q
authors.initials: EQ
authors.lastname: Comeaux
authors.forename: Robert C A M
authors.initials: RC
authors.lastname: van Waardenburg
mesh_terms: D000818:Animals; D055162:Biocatalysis; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018736:DNA Adducts; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: Camptothecins; DNA adducts; DNA metabolism; DNA topoisomerases; Tdp1; etoposide; oxidative DNA damage; structure–function