Probing the evolutionary conserved residues Y204, F259, S400 and W590 that shape the catalytic groove of human TDP1 for 3'- and 5'-phosphodiester-DNA bond cleavage.

ABSTRACT: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an ubiquitous DNA repair enzyme present in yeast, plants and animals. It removes a broad range of blocking lesions at the ends of DNA breaks. The catalytic core of TDP1 consists in a pair of conserved histidine-lysine-asparagine (HKN) motifs. Analysis of the human TDP1 (hTDP1) crystal structure reveals potential involvement of additional residues that shape the substrate binding site. In this biochemical study, we analyzed four such conserved residues, tyrosine 204 (Y204), phenylalanine 259 (F259), serine 400 (S400) and tryptophan 590 (W590). We show that the F259 residue of hTDP1 is critical for both 3'- and 5'-phosphodiesterase catalysis. We propose that the double π-π interactions of the F259 residue with the -2 and -3 nucleobases serve to posit

SUBMITTER: Kiselev E 

PROVIDER: S-EPMC8057126 | biostudies-literature | 2018 Jun - Jul

REPOSITORIES: biostudies-literature