Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) inhibitors

Huang, Shar-yin N.; Pommier, ﻿Yves; Marchand, Christophe

doi:10.1517/13543776.2011.604314

Cited by 82 publications

(76 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Replication-induced DSBs are repaired by homologous recombination, which explains the hypersensitivity of BRCA-deficient cancer cells to Top1cc-targeted drugs [27]. Top1-DNA covalent complexes can be removed by two pathways: 1/excision of Top1 by TDP1 [28], and 2/DNA cleavage by 3′-flap endonucleases such as XPF-ERCC1 [29] (Fig. 2A).…”

Section: Topoisomerase Cleavage Complexesmentioning

confidence: 99%

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

et al. 2014

Self Cite

View full text Add to dashboard Cite

TDP1 and TDP2 were discovered and named based on the fact they process 3′- and 5′-DNA ends by excising irreversible protein tyrosyl-DNA complexes involving topoisomerases I and II, respectively. Yet, both enzymes have an extended spectrum of activities. TDP1 not only excises trapped topoisomerases I (Top1 in the nucleus and Top1mt in mitochondria), but also repairs oxidative damage-induced 3′-phosphoglycolates and alkylation damage-induced DNA breaks, and excises chain terminating anticancer and antiviral nucleosides in the nucleus and mitochondria. The repair function of TDP2 is devoted to the excision of topoisomerase II- and potentially topoisomerases III-DNA adducts. TDP2 is also essential for the life cycle of picornaviruses (important human and bovine pathogens) as it unlinks VPg proteins from the 5′-end of the viral RNA genome. Moreover, TDP2 has been involved in signal transduction (under the former names of TTRAP or EAPII). The DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway. By contrast, TDP2 repair functions are coordinated with Ku and ligase IV in the non-homologous end joining pathway (NHEJ). This article summarizes and compares the biochemistry, functions, and post-translational regulation of TDP1 and TDP2, as well as the relevance of TDP1 and TDP2 as determinants of response to anticancer agents. We discuss the rationale for developing TDP inhibitors for combinations with topoisomerase inhibitors (topotecan, irinotecan, doxorubicin, etoposide, mitoxantrone) and DNA damaging agents (temozolomide, bleomycin, cytarabine, and ionizing radiation), and as novel antiviral agents.

show abstract

Section: Topoisomerase Cleavage Complexesmentioning

confidence: 99%

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…First, the dCIN phenotype induced by Tdp1 overexpression could affect the efficacy of drug response. As well, the biochemical assays used to screen for Tdp1 inhibitors rely on catalytic activity, with the most potent Tdp1 inhibitors uncovered to date being nonhydrolysable substrate mimetics (89,98,99). But these inhibitors may not be effective in vivo if only Tdp1 activity is targeted without influencing the affinity of Tdp1 binding to the DNA.…”

Section: Sdl Screens As a Platform To Identify Therapeutic Targets Inmentioning

confidence: 99%

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Duffy

Fam

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.dosage chromosome instability | overexpression | synthetic dosage lethality | TDP1 | rhabdomyosarcoma

show abstract

“…Previous molecular modelling studies strongly indicate that hydrogen bonding to Histidine 263 is required for effective inhibition. 5,12 Also, the hydrophobic pocket in the binding site is occupied by the terpene moiety. It can therefore be stated that a plausible binding mode is predicted.…”

Section: Molecular Modellingmentioning

confidence: 99%