title: Tyrosyl-DNA phosphodiesterase 1 initiates repair of apurinic/apyrimidinic sites.
abstract: Tyrosyl-DNA phosphodiesterase 1 (Tdp1) catalyzes the hydrolysis of the phosphodiester linkage between the DNA 3' phosphate and a tyrosine residue as well as a variety of other DNA 3' damaged termini. Recently we have shown that Tdp1 can liberate the 3' DNA phosphate termini from apurinic/apyrimidinic (AP) sites. Here, we found that Tdp1 is more active in the cleavage of the AP sites inside bubble-DNA structure in comparison to ssDNA containing AP site. Furthermore, Tdp1 hydrolyzes AP sites opposite to bulky fluorescein adduct faster than AP sites located in dsDNA. Whilst the Tdp1 H493R (SCAN1) and H263A mutants retain the ability to bind an AP site-containing DNA, both mutants do not reveal endonuclease activity, further suggesting the specificity of the AP cleavage activity. We suggest that this Tdp1 activity can contribute to the repair of AP sites particularly in DNA structures containing ssDNA region or AP sites in the context of clustered DNA lesions.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Lavrentiev av. 8, 630090 Novosibirsk, Russia.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Lebedeva
authors.forename: Nadejda I
authors.initials: NI
authors.lastname: Rechkunova
authors.forename: Sherif F
authors.initials: SF
authors.lastname: El-Khamisy
authors.forename: Olga I
authors.initials: OI
authors.lastname: Lavrik
mesh_terms: D001080:Apurinic Acid / Q000737:chemistry*; D001665:Binding Sites; D002384:Catalysis; D004247:DNA / Q000737:chemistry; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D009690:Nucleic Acid Conformation; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D011119:Polynucleotides / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D004268:DNA-Binding Proteins; D011119:Polynucleotides; C001790:apyrimidinic acid; D001080:Apurinic Acid; D004247:DNA; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human