Research Paper Volume 13, Issue 12 pp 15917—15941
Differential responses of neurons, astrocytes, and microglia to G-quadruplex stabilization
- 1 Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA
- 2 Institut de Chimie Moléculaire (ICMUB), UBFC Dijon, CNRS UMR6302, Dijon, France
- 3 Shared Equipment Authority, Rice University, Houston, TX 77005, USA
- 4 Biostatistics and Epidemiology Research Design Core Center for Clinical and Translational Sciences, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA
- 5 Department of Internal Medicine, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA
- 6 The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA
- 7 UTHealth Consortium on Aging, The University of Texas McGovern Medical School, Houston, TX 77030, USA
Received: March 19, 2021 Accepted: June 12, 2021 Published: June 19, 2021
https://doi.org/10.18632/aging.203222How to Cite
Copyright: © 2021 Tabor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The G-quadruplex (G4-DNA or G4) is a secondary DNA structure formed by DNA sequences containing multiple runs of guanines. 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. We previously showed that, in cultured primary neurons, small-molecule G4 stabilizers promote formation of DNA double-strand breaks (DSBs) and downregulate the Brca1 gene. Here, we determined if G4-dependent Brca1 downregulation is unique to neurons or if the effects in neurons also occur in astrocytes and microglia. We show that primary neurons, astrocytes and microglia basally exhibit different G4 landscapes. Stabilizing G4-DNA with the G4 ligand pyridostatin (PDS) 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. Taken together, our findings suggest that stabilized G4-DNA contribute to genomic instability in the brain and may represent a novel senescence pathway in brain aging.