Biology subjects

Matsuda, A.

Publications and source records attributed to Matsuda, A..

3 recordsLinked to original sources

bioRxiv2021

Acriflavine, a clinically aproved drug, inhibits SARS-CoV-2 and other betacoronaviruses

SO_SCPLOWUMMARYC_SCPLOWThe COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identified acriflavine as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

microbiology↗

bioRxiv2020

Surprising Phenotypic Diversity of Cancer-associated mutations of Gly 34 in the Histone H3 tail

Sequencing of cancer genomes has identified recurrent somatic mutations in histones, termed oncohistones, which are frequently poorly understood. Previously we showed that fission yeast expressing only the H3.3G34R mutant identified in aggressive pediatric glioma had reduced H3K36 trimethylation and acetylation, increased genomic instability and replicative stress, and defective homology-dependent DNA damage repair (Yadav et al., 2017). Here we show that surprisingly distinct phenotypes result from G34V (also in glioma) and G34W (giant cell tumors of bone) mutations, differentially affecting H3K36 modifications, subtelomeric silencing, genomic stability, sensitivity to irradiation, alkylating agents, hydroxyurea and influencing DNA repair. In cancer, only one of thirty alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity and homologous recombination defects, and dominant subtelomeric silencing. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in H3 and highlight the utility of genetically tractable systems for their analysis.

molecular biology↗

bioRxiv2020

The Linear Element is a Stable Structure Along the Chromosome Axis in Fission Yeast

Chromosomes structure changes dramatically upon entering meiosis to ensure the successful progression of meiosis-specific events. During this process, a multilayer proteinaceous structure called synaptonemal complex (SC) is formed in many eukaryotes. Instead, in the fission yeast Schizosaccharomyces pombe, linear elements (LinEs), which are structures related to an axial element of SC, form on the meiotic cohesin-based chromosome axis and are required for the formation of DNA double-strand breaks. In contrast to the well-organized SC structure, LinE structure had been observed only by silver-stained electron micrographs or in immuno-fluorescence stained spread nuclei. Thus, their fine structure and dynamics in intact living cells remain to be elucidated. In this study, we performed live cell imaging with wide-field fluorescence microscopy as well as 3D structured illumination microscopy (3D-SIM) for the four components of LinE, the Rec10, Rec25, Rec27 and Mug20. We found that LinEs consist of threads formed along the chromosome axes during the meiotic prophase. Rec10 binds to the chromosome itself and shapes into LinEs only in the presence of all the other LinE components. Rec25, Rec27, and Mug20 attach to the chromosome in the presence of Rec10. LinEs are stable in a short-time treatment with 1,6-hexanediol; and fluorescence recovery after photobleaching (FRAP) experiment reveals slow recovery from photobleaching, indicating a stable property of LinEs.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗