A5074228660- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Cancer therapeutics and mechanisms
- Ovarian cancer diagnosis and treatment
- Synthesis and Catalytic Reactions
- Protein Degradation and Inhibitors
- CRISPR and Genetic Engineering
- Histone Deacetylase Inhibitors Research
- RNA modifications and cancer
- Synthesis of β-Lactam Compounds
- Synthesis and Biological Evaluation
- Signaling Pathways in Disease
- Cancer Genomics and Diagnostics
- Integrated Circuits and Semiconductor Failure Analysis
- Lung Cancer Research Studies
- Computational Drug Discovery Methods
- TGF-β signaling in diseases
- Bioactive Compounds and Antitumor Agents
- Epigenetics and DNA Methylation
- Glioma Diagnosis and Treatment
- Immune cells in cancer
- Chemical Reactions and Isotopes
- Click Chemistry and Applications
- Genomics and Phylogenetic Studies
- RNA Research and Splicing
Kyoto University
2011-2025
Keio University
2019-2025
Ehime University
2022-2025
Institute for Advanced Medical Research
2024
Center for Cancer Research
2012-2023
National Institutes of Health
2012-2023
Niigata University Medical and Dental Hospital
2022
Ehime Medical Center
2022
Keio University Shonan Fujisawa
2020-2021
National Cancer Institute
2012-2020
Abstract Small-molecule inhibitors of PARP are thought to mediate their antitumor effects as catalytic that block repair DNA single-strand breaks (SSB). However, the mechanism action with regard in cancer cells is not fully understood. In this study, we show trap PARP1 and PARP2 enzymes at damaged DNA. Trapped PARP–DNA complexes were more cytotoxic than unrepaired SSBs caused by inactivation, arguing act part poisons enzyme on Moreover, potency trapping differed markedly among niraparib...
Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP have an additional cytotoxic mechanism by trapping PARP-DNA complexes, and both olaparib niraparib act poisons at pharmacologic concentrations. Therefore, we proposed should be evaluated based on inhibition trapping. Here, novel inhibitor, BMN 673, compared its effects PARP1 PARP2 with two other clinical inhibitors, rucaparib, using...
We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to NAD<sup>+</sup>-competitive catalytic inhibitory mechanism. PARP is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent inhibitors. Here, we evaluated the combination of or veliparib therapeutically relevant DNA-targeted drugs, including topoisomerase I inhibitor camptothecin, alkylating...
// Junko Murai 1 , Ying Feng 2 Guoying K. Yu Yuanbin Ru Sai-Wen Tang 1,3 Yuqiao Shen and Yves Pommier Developmental Therapeutics Branch Laboratory of Molecular Pharmacology, Center for Cancer Research, National Institute, Institutes Health, Bethesda, MD, USA BioMarin Pharmaceutical Inc., Novato, CA, 3 Current affiliation: Division Blood Marrow Transplantation, Department Medicine, Stranford University School Stanford, Correspondence to: Pommier, email: Keywords : PARP-trapping, ATR, PARP...
Abstract In this study, overexpression of noggin, a BMP antagonist, in developing bone caused significantly decreased osteoclast number as well formation rate, resulting increased mass with immature quality. signaling plays important roles normal development and regulation resorption. Introduction: Bone morphogenetic proteins (BMPs) act on various types cells. Although involvement signals osteoblast differentiation has been studied extensively, the effects BMPs osteoclasts have not widely...
Abstract Poly(ADP-ribose) polymerases (PARP) attach poly(ADP-ribose) (PAR) chains to various proteins including themselves and chromatin. Topoisomerase I (Top1) regulates DNA supercoiling is the target of camptothecin indenoisoquinoline anticancer drugs, as it forms Top1 cleavage complexes (Top1cc) that are trapped by drugs. Endogenous carcinogenic lesions can also trap Top1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1), a key repair enzyme for Top1cc, hydrolyzes phosphodiester bond between...
Clinical topoisomerase I (Top1) and II (Top2) inhibitors trap topoisomerases on DNA, thereby inducing protein-linked DNA breaks. Cancer cells resist the drugs by removing topoisomerase-DNA complexes, repairing drug-induced double-strand breaks (DSB) homologous recombination nonhomologous end joining (NHEJ). Because numerous enzymes cofactors are involved in removal of complexes DSB repair, it has been challenging to comprehensively analyze relative contribution multiple genetic pathways...
Protein ubiquitination plays a key role in the regulation of variety DNA repair mechanisms. is controlled by coordinate activity ubiquitin ligases and deubiquitinating enzymes (DUBs). The enzyme USP1 regulates Fanconi anemia pathway through its association with WD40 binding partner, UAF1, deubiquitination two critical proteins, FANCD2-Ub PCNA-Ub. To investigate function we generated USP1−/−, UAF1−/−/−, USP1−/− UAF1−/−/− chicken DT40 cell clones. These three clones showed similar...
Poly(ADP-ribose) polymerase inhibitors (PARPis) have recently been approved for the treatment of ovarian and breast cancers with BRCA mutations, as well maintenance therapies regardless mutation primary peritoneal that previously responded to platinum-based chemotherapy. The rationale these indications is derived from facts cancer cells mutations are defective in homologous recombination (HR), which confers synthetic lethality PARPis, some sensitivity-determining factors PARPis shared...
Significance Schlafen-11 (SLFN11) inactivation leads to chemoresistance of a broad range DNA-damaging agents. We uncover an expanded Ataxia Telangiectasia- and Rad3-related (ATR)-mediated signaling network that overcomes by unbiased genome-wide RNAi screen in SLFN11 -knockout cells is validated with clinically developing ATR/CHK1 inhibitors. ATR inhibition induces CDT1 phosphorylation, leading mitotic catastrophe cell death SLFN11-deficient cells. identify key role for degradation binding...
Impairment of ribosome biogenesis (RiBi) triggered by inhibition ribosomal RNA (rRNA) synthesis and processing leads to various biological effects. We report that Schlafen 11 (SLFN11) induces TP53-independent apoptosis through RiBi impairment. Upon replication stress, SLFN11 inhibits rRNA with polymerase I accumulation increased chromatin accessibility in the DNA (rDNA) genes. SLFN11-dependent impairment preferentially depletes short-lived proteins, particularly MCL1, leading response...
The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How is targeted to FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 SLD2). SLD2 binds directly domain-interacting motif (SIM) on FANCI. Deletion sequence or mutation SIM FANCI disrupts UAF1/FANCI binding inhibits FANCD2 deubiquitination also PCNA-Ub, requires...
The abortive activity of topoisomerases can result in clastogenic and/or lethal DNA damage which the topoisomerase is covalently linked to 3′- or 5′-terminus a strand break. This type implicated chromosome translocations and neurological disease underlies clinical efficacy an important class anticancer 'poisons'. Tyrosyl phosphodiesterase-1 protects cells from I (Top1) by hydrolyzing 3′-phosphotyrosyl bond that links Top1 break currently only known human enzyme displays this cells. Recently,...
Chain-terminating nucleoside analogs (CTNAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the damage induced by these Here, we reveal importance tyrosyl–DNA phosphodiesterase 1 (TDP1) in nuclear mitochondrial CTNAs. On investigating effects four CTNAs—acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) zalcitabine (ddC)—we show TDP1 capable removing covalently...
SLFN11 was identified as a critical determinant of response to DNA-targeted therapies by analyzing gene expression and drug sensitivity NCI-60 CCLE datasets. However, how is regulated in cancer cells remained unknown. Ewing sarcoma, which characterized the chimeric transcription factor EWS-FLI1, has notably high expression, leading us investigate whether EWS-FLI1 drives role sarcoma cells.Binding sites on promoter were analyzed chromatin immunoprecipitation sequencing promoter-luciferase...
Abstract Purpose: Schlafen 11 (SLFN11), a putative DNA/RNA helicase is dominant genomic determinant of response to DNA-damaging agents and frequently not expressed in cancer cells. Whether histone deacetylase (HDAC) inhibitors can be used release SLFN11 sensitize SLFN11-inactivated cancers DNA-targeted tested here. Experimental Design: expression was examined The Cancer Genome Atlas (TCGA), cell line databases patients treated with romidepsin. Isogenic cells overexpressing or genetically...
Schlafen 11 (SLFN11) was recently discovered as a cellular restriction factor against replication stress. Here, we show that SLFN11 increases chromatin accessibility genome wide, prominently at active promoters in response to stress induced by the checkpoint kinase 1 (CHK1) inhibitor prexasertib or topoisomerase I (TOP1) camptothecin. Concomitantly, selectively activates pathways inducing transcription of immediate early genes (IEGs), including JUN, FOS, EGR1, NFKB2, and ATF3, together with...