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Yves Pommier, Yilun Sun, Shar-Yin N Huang, John L Nitiss
Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 and by endonucleases (MRE11, XPF-ERCC1 and MUS81)...
September 21, 2016: Nature Reviews. Molecular Cell Biology
Timsi Rao, Rui Gao, Saeko Takada, Muthana Al Abo, Xiang Chen, Kylie J Walters, Yves Pommier, Hideki Aihara
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...
August 19, 2016: Nucleic Acids Research
Bradley R Kossmann, Monica Abdelmalak, Sophia Lopez, Gabrielle Tender, Chunli Yan, Yves Pommier, Christophe Marchand, Ivaylo Ivanov
Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft...
July 15, 2016: Bioorganic & Medicinal Chemistry Letters
Vijay Menon, Lawrence F Povirk
Nonhomologous end joining (NHEJ) is an error-prone DNA double-strand break repair pathway that is active throughout the cell cycle. A substantial fraction of NHEJ repair events show deletions and, less often, insertions in the repair joints, suggesting an end-processing step comprising the removal of mismatched or damaged nucleotides by nucleases and other phosphodiesterases, as well as subsequent strand extension by polymerases. A wide range of nucleases, including Artemis, Metnase, APLF, Mre11, CtIP, APE1, APE2 and WRN, are biochemically competent to carry out such double-strand break end processing, and have been implicated in NHEJ by at least circumstantial evidence...
July 2016: DNA Repair
Yasemin Saygideger Kont, Arijit Dutta, Apurva Mallisetty, Jeena Mathew, Tsion Minas, Christina Kraus, Priyanka Dhopeshwarkar, Bhaskar Kallakury, Sankar Mitra, Aykut Üren, Sanjay Adhikari
DNA topoisomerase 2 (Top2) poisons, including common anticancer drugs etoposide and doxorubicin kill cancer cells by stabilizing covalent Top2-tyrosyl-DNA 5'-phosphodiester adducts and DNA double-strand breaks (DSBs). Proteolytic degradation of the covalently attached Top2 leaves a 5'-tyrosylated blocked termini which is removed by tyrosyl DNA phosphodiesterase 2 (TDP2), prior to DSB repair through non-homologous end joining (NHEJ). Thus, TDP2 confers resistance of tumor cells to Top2-poisons by repairing such covalent DNA-protein adducts, and its pharmacological inhibition could enhance the efficacy of Top2-poisons...
July 2016: DNA Repair
Waheba Elsayed, Lamia El-Shafie, Mohamed K Hassan, Mohamed A Farag, Sherif F El-Khamisy
Camptothecin (CPT), a topoisomerase I (TOP1) inhibitor, exhibits anti-tumor activity against a wide range of tumors. Redundancy of TOP1-mediated repair mechanisms is a major challenge facing the efficiency of TOP1-targetting therapies. This study aims to uncover new TOP1 targeting approaches utilising a selection of natural compounds in the presence or absence of tyrosyl DNA phosphodiesterase I (TDP1); a key TOP1-mediated protein-linked DNA break (PDB) repair enzyme. We identify, isoeugenol, a phenolic ether found in plant essential oils, as a potentiator of CPT cytotoxicity in Tdp1 deficient but not proficient cells...
2016: Scientific Reports
Christophe Marchand, Monica Abdelmalak, Jayakanth Kankanala, Shar-Yin Huang, Evgeny Kiselev, Katherine Fesen, Kayo Kurahashi, Hiroyuki Sasanuma, Shunichi Takeda, Hideki Aihara, Zhengqiang Wang, Yves Pommier
Tyrosyl-DNA phosphodiesterase 2 repairs irreversible topoisomerase II-mediated cleavage complexes generated by anticancer topoisomerase-targeted drugs and processes replication intermediates for picornaviruses (VPg unlinkase) and hepatitis B virus. There is currently no TDP2 inhibitor in clinical development. Here, we report a series of deazaflavin derivatives that selectively inhibit the human TDP2 enzyme in a competitive manner both with recombinant and native TDP2. We show that mouse, fish, and C. elegans TDP2 enzymes are highly resistant to the drugs and that key protein residues are responsible for drug resistance...
July 15, 2016: ACS Chemical Biology
Peter Hornyak, Trevor Askwith, Sarah Walker, Emilia Komulainen, Michael Paradowski, Lewis E Pennicott, Edward J Bartlett, Nigel C Brissett, Ali Raoof, Mandy Watson, Allan M Jordan, Donald J Ogilvie, Simon E Ward, John R Atack, Laurence H Pearl, Keith W Caldecott, Antony W Oliver
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5'-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain...
July 1, 2016: Biochemical Journal
Matthew J Schellenberg, Lalith Perera, Christina N Strom, Crystal A Waters, Brinda Monian, C Denise Appel, Caroline K Vilas, Jason G Williams, Dale A Ramsden, R Scott Williams
Mammalian Tyrosyl-DNA phosphodiesterase 2 (Tdp2) reverses Topoisomerase 2 (Top2) DNA-protein crosslinks triggered by Top2 engagement of DNA damage or poisoning by anticancer drugs. Tdp2 deficiencies are linked to neurological disease and cellular sensitivity to Top2 poisons. Herein, we report X-ray crystal structures of ligand-free Tdp2 and Tdp2-DNA complexes with alkylated and abasic DNA that unveil a dynamic Tdp2 active site lid and deep substrate binding trench well-suited for engaging the diverse DNA damage triggers of abortive Top2 reactions...
May 5, 2016: Nucleic Acids Research
Jayakanth Kankanala, Christophe Marchand, Monica Abdelmalak, Hideki Aihara, Yves Pommier, Zhengqiang Wang
Tyrosyl DNA phosphodiesterase II (TDP2) is a recently discovered enzyme that specifically repairs DNA damages induced by topoisomerase II (Top2) poisons and causes resistance to these drugs. Inhibiting TDP2 is expected to enhance the efficacy of clinically important Top2-targeting anticancer drugs. However, TDP2 as a therapeutic target remains poorly understood. We report herein the discovery of isoquinoline-1,3-dione as a viable chemotype for selectively inhibiting TDP2. The initial hit compound 43 was identified by screening our in-house collection of synthetic compounds...
March 24, 2016: Journal of Medicinal Chemistry
Daniel E Beck, Wei Lv, Monica Abdelmalak, Caroline B Plescia, Keli Agama, Christophe Marchand, Yves Pommier, Mark Cushman
Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds' activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human cancer cell cultures...
April 1, 2016: Bioorganic & Medicinal Chemistry
Ka Bian, Naveen Reddy Muppani, Lobna Elkhadragy, Wei Wang, Cheng Zhang, Tenghui Chen, Sungyun Jung, Ole Morten Seternes, Weiwen Long
Posttranslational modifications (PTMs), such as phosphorylation and ubiquitination, play critical regulatory roles in the assembly of DNA damage response proteins on the DNA damage site and their activities in DNA damage repair. Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, thereby protecting cancer cells against Top2 inhibitors-induced growth inhibition and cell death. The regulation of TDP2 activity by post-translational modifications in DNA repair, however, remains unclear...
February 9, 2016: Oncotarget
Yukiko Kametani, Chiaki Takahata, Takashi Narita, Kiyoji Tanaka, Shigenori Iwai, Isao Kuraoka
Etoposide is a widely used anticancer drug and a DNA topoisomerase II (Top2) inhibitor. Etoposide produces Top2-attached single-strand breaks (Top2-SSB complex) and double-strand breaks (Top2-DSB complex) that are thought to induce cell death in tumor cells. The Top2-SSB complex is more abundant than the Top2-DSB complex. Human tyrosyl-DNA phosphodiesterase 2 (TDP2) is required for efficient repair of Top2-DSB complexes. However, the identities of the proteins involved in the repair of Top2-SSB complexes are unknown, although yeast genetic data indicate that 5' to 3' structure-specific DNA endonuclease activity is required for alternative repair of Top2 DNA damage...
January 2016: Carcinogenesis
Xiuji Cui, Rebecca McAllister, Rajeev Boregowda, Ji A Sohn, Felipe Cortes Ledesma, Keith W Caldecott, Christoph Seeger, Jianming Hu
Hepatitis B virus (HBV) replication and persistence are sustained by a nuclear episome, the covalently closed circular (CCC) DNA, which serves as the transcriptional template for all viral RNAs. CCC DNA is converted from a relaxed circular (RC) DNA in the virion early during infection as well as from RC DNA in intracellular progeny nucleocapsids via an intracellular amplification pathway. Current antiviral therapies suppress viral replication but cannot eliminate CCC DNA. Thus, persistence of CCC DNA remains an obstacle toward curing chronic HBV infection...
2015: PloS One
Christian Königer, Ida Wingert, Moritz Marsmann, Christine Rösler, Jürgen Beck, Michael Nassal
Hepatitis B virus (HBV), the causative agent of chronic hepatitis B and prototypic hepadnavirus, is a small DNA virus that replicates by protein-primed reverse transcription. The product is a 3-kb relaxed circular DNA (RC-DNA) in which one strand is linked to the viral polymerase (P protein) through a tyrosyl-DNA phosphodiester bond. Upon infection, the incoming RC-DNA is converted into covalently closed circular (ccc) DNA, which serves as a viral persistence reservoir that is refractory to current anti-HBV treatments...
October 7, 2014: Proceedings of the National Academy of Sciences of the United States of America
Sara N Andres, Matthew J Schellenberg, Bret D Wallace, Percy Tumbale, R Scott Williams
Exposure to environmental toxicants and stressors, radiation, pharmaceutical drugs, inflammation, cellular respiration, and routine DNA metabolism all lead to the production of cytotoxic DNA strand breaks. Akin to splintered wood, DNA breaks are not "clean." Rather, DNA breaks typically lack DNA 5'-phosphate and 3'-hydroxyl moieties required for DNA synthesis and DNA ligation. Failure to resolve damage at DNA ends can lead to abnormal DNA replication and repair, and is associated with genomic instability, mutagenesis, neurological disease, ageing and carcinogenesis...
January 2015: Environmental and Molecular Mutagenesis
Christophe Marchand, Shar-yin N Huang, Thomas S Dexheimer, Wendy A Lea, Bryan T Mott, Adel Chergui, Alena Naumova, Andrew G Stephen, Andrew S Rosenthal, Ganesha Rai, Junko Murai, Rui Gao, David J Maloney, Ajit Jadhav, William L Jorgensen, Anton Simeonov, Yves Pommier
Drug screening against novel targets is warranted to generate biochemical probes and new therapeutic drug leads. TDP1 and TDP2 are two DNA repair enzymes that have yet to be successfully targeted. TDP1 repairs topoisomerase I-, alkylation-, and chain terminator-induced DNA damage, whereas TDP2 repairs topoisomerase II-induced DNA damage. Here, we report the quantitative high-throughput screening (qHTS) of the NIH Molecular Libraries Small Molecule Repository using recombinant human TDP1. We also developed a secondary screening method using a multiple loading gel-based assay where recombinant TDP1 is replaced by whole cell extract (WCE) from genetically engineered DT40 cells...
August 2014: Molecular Cancer Therapeutics
Yves Pommier, Shar-yin N Huang, Rui Gao, Benu Brata Das, Junko Murai, Christophe Marchand
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...
July 2014: DNA Repair
Rui Gao, Matthew J Schellenberg, Shar-Yin N Huang, Monica Abdelmalak, Christophe Marchand, Karin C Nitiss, John L Nitiss, R Scott Williams, Yves Pommier
Eukaryotic type II topoisomerases (Top2α and Top2β) are homodimeric enzymes; they are essential for altering DNA topology by the formation of normally transient double strand DNA cleavage. Anticancer drugs (etoposide, doxorubicin, and mitoxantrone) and also Top2 oxidation and DNA helical alterations cause potentially irreversible Top2·DNA cleavage complexes (Top2cc), leading to Top2-linked DNA breaks. Top2cc are the therapeutic mechanism for killing cancer cells. Yet Top2cc can also generate recombination, translocations, and apoptosis in normal cells...
June 27, 2014: Journal of Biological Chemistry
Peter J McKinnon
No abstract text is available yet for this article.
May 2014: Nature Genetics
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