Structural basis for recognition of 5'-phosphotyrosine adducts by Tdp2
- Authors
- Shi, K., Kurahashi, K., Gao, R., Tsutakawa, S.E., Tainer, J.A., Pommier, Y., and Aihara, H.
- ID
- ZDB-PUB-121116-3
- Date
- 2012
- Source
- Nature structural & molecular biology 19(12): 1372-1377 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Humans
- Models, Molecular
- Nuclear Proteins/chemistry*
- Nuclear Proteins/metabolism
- Phosphotyrosine/chemistry*
- Signal Transduction
- Transcription Factors/chemistry*
- Transcription Factors/metabolism
- Zebrafish
- PubMed
- 23104058 Full text @ Nat. Struct. Mol. Biol.
The DNA-repair enzyme Tdp2 resolves 52-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 52 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.