The key DNA repair enzyme DNA-PKcs has several and important cellular functions. Loss of DNA-PKcs activity in mice has revealed essential roles in immune and nervous systems. In humans, DNA-PKcs is a critical factor for brain development and function since mutation of the prkdc gene causes severe neurological deficits such as microcephaly and seizures, predicting yet unknown roles of DNA-PKcs in neurons. Here we show that DNA-PKcs modulates synaptic plasticity. We demonstrate that DNA-PKcs localizes at synapses and phosphorylates PSD-95 at newly identified residues controlling PSD-95 protein stability. DNA-PKcs -/- mice are characterized by impaired Long-Term Potentiation (LTP), changes in neuronal morphology, and reduced levels of postsynaptic proteins. A PSD-95 mutant that is constitutively phosphorylated rescues LTP impairment when over-expressed in DNA-PKcs -/- mice. Our study identifies an emergent physiological function of DNA-PKcs in regulating neuronal plasticity, beyond genome stability.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11315936 | PMC |
| http://dx.doi.org/10.1038/s44319-024-00198-3 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations.
Nat Biotechnol
November 2024
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Article Synopsis
- The DNA-PKcs inhibitor AZD7648 improves the efficiency of CRISPR-Cas9 gene editing for homology-directed repair, showing promise for clinical use.
- However, the use of AZD7648 may lead to significant unintended outcomes such as large deletions, loss of chromosome arms, and chromosomal rearrangements.
- These large-scale genetic changes may go undetected by standard editing tests, highlighting the need for further investigation into the potential risks associated with using AZD7648 in genome editing.
The interplay of DNA repair context with target sequence predictably biases Cas9-generated mutations.
Nat Commun
November 2024
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Article Synopsis
- The study investigates how the surrounding DNA sequence affects the repair of double-stranded breaks caused by CRISPR/Cas9, using various genetically modified mouse embryonic stem cell lines.
- Researchers analyzed over 236,000 mutation outcomes from 2800 synthetic DNA sequences, discovering specific roles of DNA repair proteins like Prkdc and Polm in generating small insertions and deletions.
- They developed predictive models for these mutational outcomes based on their findings, enhancing the understanding of DNA repair mechanisms and enabling more accurate control of CRISPR-induced mutations.
Making PI3K superfamily enzymes run faster.
Adv Biol Regul
November 2024
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. Electronic address:
Article Synopsis
- The phosphoinositide 3-kinase (PI3K) superfamily consists of lipid kinases and PI3K-like protein kinases that share a conserved C-terminal kinase domain, characterized by low basal activity that can be significantly enhanced by various regulatory factors.
- Activators induce conformational changes in the kinase domain that improve ATP-binding and catalysis efficiency, specifically through realignment of the active site and changes in a region known as the PIKK regulatory domain.
- A recent discovery of a small-molecule activator for PI3Kα may lead to the development of specific PI3K activators, with potential applications in wound healing, neurodegeneration treatment, and anti-stroke therapies.
NU7441, a selective inhibitor of DNA-PKcs, alleviates intracerebral hemorrhage injury with suppression of ferroptosis in brain.
PeerJ
November 2024
Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Neuronal apoptosis, oxidative stress, and ferroptosis play a crucial role in the progression of secondary brain injury following intracerebral hemorrhage (ICH). Although studies have highlighted the important functions of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in various experimental models, its precise role and mechanism in ICH remain unclear. In this study, we investigated the effects of DNA-PKcs on N2A cells under a hemin-induced hemorrhagic state and a rat model of collagenase-induced ICH .
View Article and Find Full Text PDFSingle-stranded DNA with internal base modifications mediates highly efficient knock-in in primary cells using CRISPR-Cas9.
Nucleic Acids Res
December 2024
Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43215, USA.
Article Synopsis
- Researchers developed enhanced single-stranded DNA (esDNA) templates with chemical modifications that significantly improve the efficiency of genome editing when used with Cas9, achieving 2-3 times higher knock-in rates compared to standard ssDNA.
- In specific cell types, such as airway basal stem cells and CD34+ hematopoietic cells, esDNA facilitated correction of target genes (CFTR, HBB, CCR5) in over 50% of cases, indicating strong potential for therapeutic applications.
- However, esDNA wasn't effective in induced pluripotent stem cells due to the lack of the nuclease TREX1, suggesting further research is needed for scalable production of modified ssDNA for gene insertion.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!