The assembly of synaptic protein-DNA complexes by specialized proteins is critical for bringing together two distant sites within a DNA molecule or bridging two DNA molecules. The assembly of such synaptosomes is needed in numerous genetic processes requiring the interactions of two or more sites. The molecular mechanisms by which the protein brings the sites together, enabling the assembly of synaptosomes, remain unknown. Such proteins can utilize sliding, jumping, and segmental transfer pathways proposed for the single-site search process, but none of these pathways explains how the synaptosome assembles. Here we used restriction enzyme SfiI, that requires the assembly of synaptosome for DNA cleavage, as our experimental system and applied time-lapse, high-speed AFM to directly visualize the site search process accomplished by the SfiI enzyme. For the single-site SfiI-DNA complexes, we were able to directly visualize such pathways as sliding, jumping, and segmental site transfer. However, within the synaptic looped complexes, we visualized the threading and site-bound segment transfer as the synaptosome-specific search pathways for SfiI. In addition, we visualized sliding and jumping pathways for the loop dissociated complexes. Based on our data, we propose the site-search model for synaptic protein-DNA systems.
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http://dx.doi.org/10.3390/ijms23010212 | DOI Listing |
Front Biosci (Landmark Ed)
January 2025
Department of Neurology, Jinshan Hospital, Fudan University, 201508 Shanghai, China.
Background: Neuronal cholesterol deficiency may contribute to the synaptopathy observed in Alzheimer's disease (AD). However, the underlying mechanisms remain poorly understood. Intact synaptic vesicle (SV) mobility is crucial for normal synaptic function, whereas disrupted SV mobility can trigger the synaptopathy associated with AD.
View Article and Find Full Text PDFJ Neuroinflammation
January 2025
State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing, 100190, China.
Background: Deoxyribonuclease 2 (DNase II) is pivotal in the clearance of cytoplasmic double stranded DNA (dsDNA). Its deficiency incurs DNA accumulation in cytoplasm, which is a hallmark of multiple neurodegenerative diseases. Our previous study showed that neuronal DNase II deficiency drove tau hyperphosphorylation and neurodegeneration (Li et al.
View Article and Find Full Text PDFNat Commun
January 2025
Department of Pediatrics and Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA.
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrate dysregulation of genes associated with autism and cognitive impairment.
View Article and Find Full Text PDFNat Commun
January 2025
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Members of the piggyBac superfamily of DNA transposons are widely distributed in host genomes ranging from insects to mammals. The human genome has retained five piggyBac-derived genes as domesticated elements although they are no longer mobile. Here, we have investigated the transposition properties of piggyBat from Myotis lucifugus, the only known active mammalian DNA transposon, and show that its low activity in human cells is due to subterminal inhibitory DNA sequences.
View Article and Find Full Text PDFGenes (Basel)
December 2024
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
Background: (absent, small, or homeotic-like 1), a histone methyltransferase, has been identified as a high-risk gene for autism spectrum disorder (ASD). We previously showed that postnatal severe deficiency in the prefrontal cortex (PFC) of male and female mice caused seizures. However, the synaptic mechanisms underlying autism-like social deficits and seizures need to be elucidated.
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