Tyrosyl-DNA phosphodiesterase I (Tdp1) hydrolyzes 3'-phosphotyrosyl bonds to generate 3'-phosphate DNA and tyrosine in vitro. Tdp1 is involved in the repair of DNA lesions created by topoisomerase I, although the in vivo substrate is not known. Here we study the kinetic and binding properties of human Tdp1 (hTdp1) to identify appropriate 3'-phosphotyrosyl DNA substrates. Genetic studies argue that Tdp1 is involved in double and single strand break repair pathways; however, x-ray crystal structures suggest that Tdp1 can only bind single strand DNA. Separate kinetic and binding experiments show that hTdp1 has a preference for single-stranded and blunt-ended duplex substrates over nicked and tailed duplex substrate conformations. Based on these results, we present a new model to explain Tdp1/DNA binding properties. These results suggest that Tdp1 only acts upon double strand breaks in vivo, and the roles of Tdp1 in yeast and mammalian cells are discussed.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1074/jbc.M502148200 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
TDP1 represents a promising therapeutic target for overcoming tumor resistance to chemotherapeutic agents: progress and potential.
Bioorg Chem
December 2024
School of Pharmacy, Ningxia Medical University, Yinchuan 750004, PR China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area Ministry of Education, Ningxia Medical University, Yinchuan 750004, PR China; Collaborative Innovation Center for Ningxia Characteristic Traditional Chinese Medicine by Ningxia Hui Autonomous Region & Education Ministry of P.R. China, Ningxia Characteristic Traditional Chinese Medicine Modern Engineering and Technique Research Center, Ningxia Key Laboratory of Drug Development and Generic Drug Research, Key Laboratory of Ningxia Ethnomedicine Modernization, Ministry of Education, Yinchuan 750004, PR China. Electronic address:
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that plays a crucial role in repairing DNA lesions caused by the entrapment of DNA topoisomerase IB (TOP1)-DNA break-associated crosslinks. TDP1 inhibitors exhibit synergistic effects with TOP1 inhibitors in cancer cells, effectively overcoming resistance to TOP1 inhibitors. Therefore, this approach presents a promising strategy for reversing tumor resistance to TOP1 inhibitors.
View Article and Find Full Text PDFSpike-In Proteome Enhances Data-Independent Acquisition for Thermal Proteome Profiling.
Anal Chem
December 2024
Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China.
Target deconvolution is essential for elucidating the molecular mechanisms, therapeutic efficacy, and off-target toxicity of small-molecule drugs. Thermal proteome profiling (TPP) is a robust and popular method for identifying drug-protein interactions. Nevertheless, classical implementation of TPP using isobaric labeling of peptides is tedious, time-consuming, and costly.
View Article and Find Full Text PDFInsights into Nitrogen-Associated Protein 50 (NAP50) as a Tyrosyl-DNA Phosphodiesterase in Dinoflagellates.
Microorganisms
November 2024
School of Science and Technology, Hong Kong Metropolitan University, Hong Kong SAR, China.
Nitrogen-associated protein 50 (NAP50) is an abundant plastid protein with an unknown function identified in (Dinophyceae). No progress has been made in discovering the function of NAP50 since its first characterization in 2009. The present study is a continuation of work on the predicted function of NAP50.
View Article and Find Full Text PDFNovel Peptide-Drug Conjugates with Dual Anticancer Activity.
Int J Mol Sci
November 2024
Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentjev Ave., 630090 Novosibirsk, Russia.
Article Synopsis
- - Cationic antimicrobial peptides (AMPs) show potential as both antimicrobial and anticancer agents, and linking them to bioactive molecules may enhance their effectiveness in treating cancer.
- - In this study, two derivatives of usnic acid were combined with the AMP L-K6 using a new bonding method while both components demonstrated selective activity against cancer cells, specifically targeting the DNA repair enzyme TDP1.
- - The resulting conjugates showed a range of effects, from decreased activity of the original drugs to increased cytotoxicity against glioblastoma cells, suggesting enhanced therapeutic potential compared to the individual components.
Report of a novel missense TDP1 variant in a Pakistani family affected with an extremely rare disorder congenital spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1).
Mol Biol Rep
November 2024
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, Queen Square House, London, WC1N 3BG, UK.
Background: Spinocerebellar ataxia with axonal neuropathy type 1 (OMIM: 607250) is an extremely rare autosomal recessive disorder caused by a mutation in the tyrosyl-DNA phosphodiesterase 1 (TDP1) gene. Only a single missense variant (p.His493Arg) in this gene has been reported.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!