A5072036205- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Cancer therapeutics and mechanisms
- DNA and Nucleic Acid Chemistry
- Synthesis and Biological Evaluation
- Epigenetics and DNA Methylation
- Polyomavirus and related diseases
- Cell death mechanisms and regulation
- Hate Speech and Cyberbullying Detection
- Bacteriophages and microbial interactions
- Linguistics and Discourse Analysis
- Reproductive System and Pregnancy
- Chromosomal and Genetic Variations
- Carcinogens and Genotoxicity Assessment
- Bioactive Compounds and Antitumor Agents
- Neutropenia and Cancer Infections
- RNA and protein synthesis mechanisms
- Discourse Analysis in Language Studies
- Cytomegalovirus and herpesvirus research
- RNA modifications and cancer
- PARP inhibition in cancer therapy
Ihara Chemical Industry (Japan)
2025
Kyoto University
2016-2024
Memorial Sloan Kettering Cancer Center
2016-2024
Howard Hughes Medical Institute
2016-2017
DNA double-strand breaks that initiate meiotic recombination are exonucleolytically processed. This 5'→3' resection is a central, conserved feature of but remains poorly understood. To address this lack, we mapped endpoints genome-wide at high resolution in Saccharomyces cerevisiae Full-length requires Exo1 exonuclease and the DSB-responsive kinase Tel1, not Sgs1 helicase. Tel1 also promotes efficient timely initiation. Resection display pronounced heterogeneity between genomic loci reflects...
Meiotic recombination is initiated by SPO11-induced double-strand breaks (DSBs). In most mammals, the methyltransferase PRDM9 guides SPO11 targeting, and ATM kinase controls meiotic DSB numbers. Following MRE11 nuclease removal of SPO11, resected loaded with DMC1 filaments for homolog invasion. Here, we demonstrate direct detection DSBs resection using END-seq on mouse spermatocytes low sample input. We find that limits both minimum maximum lengths, whereas 53BP1, BRCA1 EXO1 play...
Significance BRCA1 plays a key role in homology-directed repair (HDR) S/G 2 -phase cells. It remains unclear why mutation carriers develop cancer predominantly breast and ovarian tissues. We revealed that physiological concentration (10 nM) of estrogens efficiently induce TOP2β-dependent DSBs the absence cells arrested G 1 phase. This genotoxicity was confirmed also 0 /G epithelial mouse mammary glands. These findings indicated contributes to DSB independent HDR. Our data suggested promotes...
The SPO11-generated DNA double-strand breaks (DSBs) that initiate meiotic recombination occur non-randomly across genomes, but mechanisms shaping their distribution and repair remain incompletely understood. Here, we expand on recent studies of nucleotide-resolution DSB maps in mouse spermatocytes. We find trimethylation histone H3 lysine 36 around hotspots is highly correlated, both spatially quantitatively, with 4, consistent coordinated formation action PRDM9-dependent modifications. In...
Exonucleolytic resection, critical to repair double-strand breaks (DSBs) by recombination, is not well understood, particularly in mammalian meiosis. Here, we define structures of resected DSBs mouse spermatocytes genome-wide at nucleotide resolution. Resection tracts averaged 1100 nt, but with substantial fine-scale heterogeneity individual hot spots. Surprisingly, EXO1 the major 5′ → 3′ exonuclease, DSB-responsive kinase ATM proved a key regulator both initiation and extension resection....
Base excision repair (BER) removes damaged bases by generating single-strand breaks (SSBs), gap-filling DNA polymerase β (POLβ), and resealing SSBs. A base-damaging agent, methyl methanesulfonate (MMS) is widely used to study BER. BER increases cellular tolerance MMS, anti-cancer drugs, temozolomide, carmustine, lomustine, clinical poly(ADP ribose)polymerase (PARP) poisons, olaparib talazoparib. The poisons stabilize PARP1/SSB complexes, inhibiting access of factors PARP1 XRCC1...
Objectives: The treatment of lower-extremity lymphedema, whether congenital or acquired, remains challenging. Long-term management aimed at reducing complications and maximizing quality life is essential. Compression stockings are crucial in this management; however, their application limited by patient experience (ease wear, texture, breathability, appearance). This highlights the need to evaluate alternative compression garments that maintain therapeutic efficacy while improving adherence....
Significance H-DNA is a non–B-form DNA structure containing intramolecular triplex and single-stranded (ssDNA) regions. H-DNA–forming motifs include polypyrimidine•polypurine mirror repeat sequences, which occur frequently in eukaryotic genomes. These have biological impacts on genome stability processes such as replication transcription, but their non-B DNA-forming potentials are not fully understood. Here, we show that the triplex-forming potential of mouse can be evaluated by...
Abstract DNA double-strand breaks (DSBs) made by SPO11 protein initiate homologous recombination during meiosis. Subsequent to strand breakage, endo- and exo-nucleases process the ends resect strands whose 5’ termini are at DSB, generating long 3’-terminal single-stranded tails that serve as substrates for exchange proteins. DSB resection is essential meiotic recombination, but a detailed understanding of its molecular mechanism currently lacking. Genomic approaches mapping DSBs endpoints,...
ABSTRACT Nucleolytic resection of DNA ends is critical for homologous recombination, but its mechanism not fully understood, particularly in mammalian meiosis. Here we examine roles the conserved MRN complex (MRE11, RAD50, and NBS1) through genome-wide analysis meiotic mice with various mutations, including several that cause chromosomal instability humans. Meiotic DSBs form at elevated levels remain unresected if Mre11 conditionally deleted, thus required both initiation regulation DSB...
Chemical modifications and adducts at DNA double-strand break (DSB) ends must be cleaned before re-joining by non-homologous end-joining (NHEJ). MRE11 nuclease is essential for efficient removal of Topoisomerase II (TOP2)-DNA from TOP2 poison-induced DSBs. However, mechanisms in recruitment to DSB sites G
ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific after loss. Here, we report that controls the early transcriptional response estrogens. This depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins breaks. When TOP2-mediated ligation fails, facilitates DSB repair. After estrogen exposure,...
Abstract With its ligand estrogen, the estrogen receptor (ER) initiates a global transcriptional program, promoting cell growth. This process involves topoisomerase 2 (TOP2), key protein in resolving topological issues during transcription by cleaving DNA duplex, passing another duplex through break, and repairing break. Recent studies revealed involvement of various repair proteins TOP2-induced breaks, suggesting potential alternative pathways cases where TOP2 is halted after cleavage....
Abstract Meiotic recombination is initiated by genome-wide SPO11-induced double-strand breaks (DSBs) that are processed MRE11-mediated release of SPO11. The DSB then resected and loaded with DMC1/RAD51 filaments invade homologous chromosome templates. In most mammals, locations (“hotspots”) determined the DNA sequence specificity PRDM9. Here, we demonstrate first direct detection meiotic DSBs resection in vertebrates performing END-seq on mouse spermatocytes using low sample input. We find...
Abstract The SPO11-generated DNA double-strand breaks (DSBs) that initiate meiotic recombination occur non-randomly across genomes, but mechanisms shaping their distribution and repair remain incompletely understood. Here, we expand on recent studies of nucleotide-resolution DSB maps in mouse spermatocytes. We find trimethylation histone H3 lysine 36 around hotspots is highly correlated, both spatially quantitatively, with 4, consistent coordinated formation action PRDM9-dependent...
Exonucleolytic resection, critical to repair double-strand breaks (DSBs) by recombination, is not well understood, particularly in mammalian meiosis. Here, we define structures of resected DSBs mouse spermatocytes genome-wide at nucleotide resolution. Resection tracts averaged 1100 nucleotides, but with substantial fine-scale heterogeneity individual hotspots. Surprisingly, EXO1 the major 5′→3′ exonuclease, DSB-responsive kinase ATM proved a key regulator both initiation and extension...
Abstract The DNA double-strand breaks that initiate homologous recombination during meiosis are subject to extensive 5′→3′ exonucleolytic processing. This resection is a central and conserved feature of recombination, yet its mechanism poorly understood. Using purpose-made deep-sequencing method, we mapped meiotic endpoints genome-wide at high spatial resolution in Saccharomyces cerevisiae . Generating full-length tracts requires Exo1 exonuclease activity the DNA-damage responsive kinase...
Homologous meiotic recombination starts with DNA double-strand breaks (DSBs) generated by SPO11 protein
Abstract Certain DNA sequences, including mirror-symmetric polypyrimidine/polypurine runs, are capable of folding into a triple-helix-containing non-B-form structure called H-DNA. Such H-DNA-forming sequences frequent in many eukaryotic genomes, mammals, and multiple lines evidence indicate that these motifs mutagenic can impinge on replication, transcription, other aspects genome function. In this study, we show the triplex-forming potential H-DNA mouse be evaluated using S1-sequencing...
Abstract Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves active catalysis topoisomerase II (TOP2) at regulatory sequences. TOP2 untangles DNAs transiently generating double‐strand breaks (DSBs), where covalently binds DSB ends. When fails rejoin, called “abortive” catalysis, resulting DSBs are repaired tyrosyl‐DNA phosphodiesterase 2 (TDP2) and non‐homologous end‐joining...
Abstract With its ligand estrogen, the estrogen receptor (ER) stimulates tumor cell growth by activating a global transcriptional program. This activation involves topoisomerase 2 (TOP2), which resolves topological problems transiently creating and re-ligating DNA double-strand breaks (DSBs). Recent studies have uncovered involvement of repair proteins in TOP2-induced DSBs. These noncanonical pathways may serve as backup processes when TOP2 is halted fails to re-ligate DSBs, but their impact...
A referendum in a manner of direct democracy has been occasionally adopted Japan for political decision. However, it may not always maximize public interest, and thus lead failure. This failure can easily emerge when those who insist controversial policy, such as politicians benefit from the use sophistry to justify policy. is because voters rationally judge policy ouing sophistry. In this research we focus on politicians' remarks related "Osaka Metropolis Concept" which voting day was 17th...