title: Structural basis for recognition of 5'-phosphotyrosine adducts by Tdp2.
abstract: The DNA-repair enzyme Tdp2 resolves 5'-phosphotyrosyl DNA adducts and mediates resistance to anticancer drugs that target covalent topoisomerase-DNA complexes. Tdp2 also participates in key signaling pathways during development and tumorigenesis and cleaves a protein-RNA linkage during picornavirus replication. The crystal structure of zebrafish Tdp2 bound to DNA reveals a deep, narrow basic groove that selectively accommodates the 5' end of single-stranded DNA in a stretched conformation. The crystal structure of the full-length Caenorhabditis elegans Tdp2 shows that this groove can also accommodate an acidic peptide stretch in vitro, with glutamate and aspartate side chains occupying the DNA backbone phosphate-binding sites. This extensive molecular mimicry suggests a potential mechanism for autoregulation and interaction of Tdp2 with phosphorylated proteins in signaling. Our study provides a framework to interrogate functions of Tdp2 and develop inhibitors for chemotherapeutic and antiviral applications.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Shi
authors.forename: Kayo
authors.initials: K
authors.lastname: Kurahashi
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.forename: Susan E
authors.initials: SE
authors.lastname: Tsutakawa
authors.forename: John A
authors.initials: JA
authors.lastname: Tainer
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Hideki
authors.initials: H
authors.lastname: Aihara
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D019000:Phosphotyrosine / Q000737:chemistry*; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D019000:Phosphotyrosine; D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human