Novel TDP2-ubiquitin interactions and their importance for the repair of topoisomerase II-mediated DNA damage
| Autor: | Xiang Chen, Saeko Takada, Timsi Rao, Yves Pommier, Kylie J. Walters, Muthana Al Abo, Rui Gao, Hideki Aihara |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Magnetic Resonance Spectroscopy HMG-box DNA Repair DNA repair DNA damage Biology Genome Integrity Repair and Replication 03 medical and health sciences 0302 clinical medicine Protein Domains Genetics Animals Humans Caenorhabditis elegans Proteins Replication protein A chemistry.chemical_classification DNA ligase Phosphoric Diester Hydrolases Ubiquitin Nuclear Proteins Molecular biology Cell biology DNA binding site DNA-Binding Proteins 030104 developmental biology DNA Topoisomerases Type II chemistry 030220 oncology & carcinogenesis DNA mismatch repair Drosophila Chickens Hydrophobic and Hydrophilic Interactions Nucleotide excision repair DNA Damage Transcription Factors |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | Tyrosyl DNA phosphodiesterase 2 (TDP2) is a multifunctional protein implicated in DNA repair, signal transduction and transcriptional regulation. In its DNA repair role, TDP2 safeguards genome integrity by hydrolyzing 5'-tyrosyl DNA adducts formed by abortive topoisomerase II (Top2) cleavage complexes to allow error-free repair of DNA double-strand breaks, thereby conferring cellular resistance against Top2 poisons. TDP2 consists of a C-terminal catalytic domain responsible for its phosphodiesterase activity, and a functionally uncharacterized N-terminal region. Here, we demonstrate that this N-terminal region contains a ubiquitin (Ub)-associated (UBA) domain capable of binding multiple forms of Ub with distinct modes of interactions and preference for either K48- or K63-linked polyUbs over monoUb. The structure of TDP2 UBA bound to monoUb shows a canonical mode of UBA-Ub interaction. However, the absence of the highly conserved MGF motif and the presence of a fourth α-helix make TDP2 UBA distinct from other known UBAs. Mutations in the TDP2 UBA-Ub binding interface do not affect nuclear import of TDP2, but severely compromise its ability to repair Top2-mediated DNA damage, thus establishing the importance of the TDP2 UBA-Ub interaction in DNA repair. The differential binding to multiple Ub forms could be important for responding to DNA damage signals under different contexts or to support the multi-functionality of TDP2. |
| Databáze: | OpenAIRE |
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