Aging-US: Responses of neurons, astrocytes, & microglia to G-quadruplex stabilization
07-25-2021Aging-US published "Differential responses of neurons, astrocytes, and microglia to G-quadruplex stabilization" which reported that while it is now firmly established that stabilized G4s lead to enhanced genomic instability in cancer cells, whether and how G4s contribute to genomic instability in brain cells is still not clear.
These authors have previously shown that, in cultured primary neurons, small-molecule G4 stabilizers promote formation of DNA double-strand breaks and downregulate the Brca1 gene.
They also show that primary neurons, astrocytes and microglia basally exhibit different G4 landscapes.
Stabilizing G4-DNA with the G4 ligand pyridostatin differentially modifies chromatin structure in these cell types.
Intriguingly, PDS promotes DNA DSBs in neurons, astrocytes and microglial cells, but fails to downregulate Brca1 in astrocytes and microglia, indicating differences in DNA damage and repair pathways between brain cell types.
PDS promotes DNA DSBs in neurons, astrocytes and microglial cells, but fails to downregulate Brca1 in astrocytes and microglia, indicating differences in DNA damage and repair pathways between brain cell types.
Dr. Andrey S. Tsvetkov from The University of Texas McGovern Medical School at Houston as well as The University of Texas Graduate School of Biomedical Science said, "Guanine (G)-rich sequences in the human genome and transcriptome can fold into non-canonical structures known as G-quadruplexes (or G4s, G4-DNA and G4-RNA, respectively)"
With G4 ChIP-seq analyses, however, the number of “active” G4-DNA structures was lower than predicted and varied between cancerous and non-cancerous tissues and between cancer cell lines, demonstrating a cell type–specific G4-DNA landscape.
G4-DNA-binding transcription factors, G4-DNA-associated proteins, and G4-DNA helicases bind to the G4-DNA structures and modulate G4 landscapes in cells.
In addition to G4s, other alternative DNA structures exist in cells, such as triplex-DNA , DNA junctions and DNA-RNA hybrids.
Figure 5. Structural equation models for executive functions and motor performance in older adults. Putative G4-forming sequences from the human, mouse, and rat Brca1 and their promoters fold into G4-DNA structures in vitro. (A) Sequences of putative G4-DNA-forming sequences from the human, mouse, and rat Brca1 and their promoters, along with their G4Hunter (GH) scores. (B, C) CD and TDS signatures of these G4-forming sequences (3 μM) in Caco.K10 buffer (10 mM lithium cacodylate buffer (pH 7.2) plus 10 mM KCl and 90 mM LiCl).
For example, stabilized G4-DNA structures favor the formation of R-loops, which promote DNA damage and amplify genome instability in cancer cells.
Errors in repairing of DNA lesions that lead to non-reversible mutations, an age-associated decrease in DNA repair capacity, and age-dependent abnormal chromatin structure all lead to neuronal dysfunction and age-associated neurodegenerative disorders.
The Tsvetkov Research Team concluded in their Aging-US Research Output, "we found that G4 landscapes differ among major brain cells—neurons, astrocytes, and microglial cells. A small-molecule ligand diminishes Brca1 expression in neurons, but not in astrocytes and microglial cells, suggesting different mechanisms in glial cells. Our data suggest that G4-DNA contributes to genomic instability in brain cells, leading to brain aging and neurodegeneration\"
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DOI - https://doi.org/10.18632/aging.203222
Full Text - https://www.aging-us.com/article/203222/text
Correspondence to: Andrey S. Tsvetkov email: andrey.s.tsvetkov@uth.tmc.edu
Keywords: G-quadruplex, DNA damage, genomic instability, neurodegeneration, Brca1
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The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.
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